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Review

Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review

by
Perihan Mutlu Erdoğan
1,2,
Funda Bilgili-Tetikoğlu
1,
Selcen Çelik-Uzuner
1,
Oktay Yıldız
3,4,5,
Sevgi Kolayli
6 and
Dimitris Mossialos
7,*
1
Department of Molecular Biology and Genetics, Faculty of Science, Karadeniz Technical University, 61080 Trabzon, Türkiye
2
Graduate School of Natural and Applied Science, Karadeniz Technical University, 61080 Trabzon, Türkiye
3
Faculty of Pharmacy, Karadeniz Technical University, 61080 Trabzon, Türkiye
4
Trabzon Teknocity, Okta R&D Eng Services Industry Trade Limited Company, 61080 Trabzon, Türkiye
5
Gumushane University, Rectorate, 29100 Gümüşhane, Türkiye
6
Department of Chemistry, Faculty of Science, Karadeniz Technical University, 61080 Trabzon, Türkiye
7
Microbial Biotechnology-Molecular Bacteriology-Virology Laboratory, Department of Biochemistry & Biotechnology, University of Thessaly, 41500 Larissa, Greece
*
Author to whom correspondence should be addressed.
Molecules 2025, 30(19), 4003; https://doi.org/10.3390/molecules30194003
Submission received: 11 August 2025 / Revised: 24 September 2025 / Accepted: 3 October 2025 / Published: 7 October 2025
(This article belongs to the Special Issue Bee Products: Recent Progress in Health Benefits Studies, 2nd Edition)

Abstract

Honey bee (Apis mellifera) products have been extensively utilized in traditional medicine. Bee venom (BV) is one of the major bee products with a high concentration of the small peptide melittin (MEL) and exerts bioactivity ranging from anti-microbial to anti-inflammatory and anti-cancer. This scoping review aims to sum up research articles on the bioactivity exerted by BV and MEL published in PubMed and Scopus from 2010 onwards. PRISMA guidelines were implemented to analyze the relevant literature; we ended up with 425 research articles. Bioactivity of BV and MEL was grouped as (i) anti-inflammatory (85), (ii) immunomodulatory (37), (iii) anti-microbial (179), (iv) anti-cancer (170), and (v) anti-oxidant (32). Although there is a significant body of research on the anti-cancer and anti-microbial activity of BV and MEL, their anti-oxidant, anti-inflammatory and immunomodulatory properties have received comparatively less attention. Many studies on the immunomodulatory effects of BV or MEL have focused on cancer. However, the effects on Parkinson’s and Alzheimer’s disease have not been extensively studied regarding the anti-inflammatory effects. Given the critical role of the immune system and inflammatory response in cancer, neurodegenerative diseases, senescence and against infections, it is paramount to further explore the immunomodulatory and anti-inflammatory potential of BV and MEL.

1. Introduction

Bee venom (BV), also known as apitoxin, is a natural mixture produced in the venom glands of bees belonging to the order Hymenoptera, which are the type of insects that generally sting their adversaries to protect themselves [1,2]. Honey bees belong to the genus Apis and are important crop pollinators, especially Apis mellifera, the European Honey Bee [1]. BV has a long history as a therapeutic substance for thousands of years, from ancient Egypt to China [2,3]. Honey bee venom is a mixture of bioactive substances such as peptides, proteins, enzymes, and other small molecules in an odorless, translucent, acidic liquid form with an average pH of 5 [4,5,6]. It is estimated that BV contains more than 200 different compounds, and more than half of them are quantified [7]. BV is harvested from honeybees with continuous electro-simulation according to the Benton protocol [8]. The most abundant BV compound is the peptide melittin (MEL), which makes up approximately 60% of dry BV weight, varying between different bee species [9,10]. The enzyme phospholipase A2 (PLA2) makes up to 20% of dry BV weight (Table 1). Another peptide, apamin, is the third most abundant compound, though it makes up to only 1% of dry BV weight, followed by approximately 200 less abundant molecules (Table 1) [7,9,10]. Numerous in vivo and in vitro studies have demonstrated that BV exerts strong bioactivity, such as anti-cancer, anti-nociceptive, anti-oxidant, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-arthritic, anti-metastatic, and hemolytic effects [5,6,11,12]. Especially in East Asia, BV is used for acupuncture to treat chronic pain, generally caused by inflammation or neuropathy [13,14].

2. Methodology

This scoping review focuses on the potentially therapeutic bioactivity exerted by the bee venom and its compounds, especially melittin, as described in original research articles. Our main goal was to implement the PRISMA guidelines to summarize and categorize the relevant scientific literature, to identify research gaps, and to suggest future perspectives on research relevant to the bioactivity exerted by BV and MEL.
The widely used Scopus and PubMed databases were searched in this review. The last search took place on 28 May 2025. Since both sites use different ID systems (EID for Scopus, PMID for PubMed), DOI links were used to store and compare the data of the documents obtained through browsing. According to our expertise on the topic, two search groups were formed, namely BV and MEL. We included general keywords to combine BV and MEL with specific types of bioactivities (Table 2). The keywords that were suggested by the databases were also considered (Table 2).
In PubMed, the search filter “best match” was applied, while in Scopus, it was “relevance”. Published articles from 2010 onwards were included. In Scopus, language was filtered with English; however, since PubMed is a US-based website, no language filter was applied. Original research and review articles were prioritized, and some literature items were considered not eligible, especially letters formatted as “letter to the editor, correction, correspondence,” etc., which don’t focus on detailed, complete research. Zotero was used as an automation program to recognize the documents and to remove duplicate results. The articles were read, categorized, and presented in tables and figures, according to their type and content.
The overall search yielded a total of 3145 items. After the 2016 duplicates and 6 publications that were marked unidentified by the automation tool were removed using Excel and Zotero, 1123 articles remained. After reviewing, 76 articles were removed because they were not original research or review articles. These publications were either letters to the editor, communications, corrections or editorials. Also, 5 articles were retracted, leaving 1044 articles for assessment for eligibility. After reviewing, the remaining 788 articles were identified as 761 research articles and 24 case reports. 425 articles were found to be relevant to our topic (Figure 1).
The remaining articles were categorized based on their type of bioactivity. BV and MEL are both used in different types of in vivo studies (clinical and animal models) as well as in vitro (cell lines, microorganisms). Types of animal models (generally rats or mice), along with administration types (injection, topical, acupuncture), targeted microorganisms, cell lines and delivery systems are listed in the experimental design section. The “additional information” column in the table provides other types of bioactivity or other specific information regarding the experimental design. It also lists the types of substances used—such as bee venom (BV), melittin, and other components of BV—along with their sources, including Apis mellifera (honeybee), general references to bees, or other species. Overall, regarding the bioactivity described or studied, the relevant articles were categorized as follows: (i) anti-inflammatory, (ii) immunomodulatory, (iii) anti-microbial, (iv) anti-cancer, and (v) anti-oxidant and they are presented below.

3. Content of Bee Venom

Bee venom consists of a range of bioactive molecules. Bee venom compounds, including melittin, apamin, secapin, mast cell degranulating (MCD) peptide, tertiapin, hyaluronidase, and phospholipase A2, act synergistically, contributing to the overall bioactivity exerted by bee venom, inducing cytolytic, neurotoxic, pro-inflammatory, allergenic, and anti-microbial effects. The most bioactive compound, Melittin (MEL), is a small peptide of 26 amino acid residues with a weight of 2840 Da (GIGAVLKVLTTGLPALISWIKRKRQQ-CONH2) and is often described as an “anti-microbial peptide (AMP)” (Figure 2A). Alongside the asymmetrical distribution of polar and non-polar amino acid residues, melittin structure demonstrates an amphipathic nature, therefore making it a highly bioactive component, especially against membranes. Therefore, melittin disrupts the membranes of cancer cells, bacteria, and fungi. In many in vitro experiments, melittin is used as a positive control for such effects. Furthermore, melittin blocks metabolic pathway elements, including Tumor Necrosis Factor (TNF) receptors, cytokine signaling pathways, and Epidermal Growth Factor Receptor (EGFR), thus suggesting its role in promoting apoptosis [1,2,3,4]. Apamin is a neurotoxin that crosses the blood–brain barrier. It contains 18 amino acid residues with two disulfide bonds (Cys1-Cys11, Cys3-Cys15) in between (Figure 2B). Since animal venom toxins are often modified post-translationally, apamin C-terminal is amidated. In the early 1980s, apamin was used to identify certain Ca2− activated K ion channels due to its selective activity towards these channels. Moreover, it is known to demonstrate antimicrobial effects. Due to molecular stability, apamin is a possible drug delivery element. Tertiapin (Figure 2C) is a 21-amino-acid peptide that blocks potassium channels [5,6,7,8]. Phospholipase A2 from bee venom (BvPLA2) is a type of secreted PLA2. BvPLA2 is Ca2+-dependent, catalyzing the hydrolysis of sn-2 acyl phospholipid bonds often implicated in inflammation, leading to the production of lysophosphatidic acid and arachidonic acid (Figure 2D). However, these interactions also exert anti-inflammatory activity from a medical perspective. Similarly to melittin, it plays a role in membrane disruption [5,9,10]. Hyaluronidase (Figure 2E) promotes allergenic response. It cleaves hyaluronan of the connective tissue and accelerates absorption of the bee venom into the tissue [5,11]. Secapin (Figure 2F) is a potential neurotoxin with anti-fibrinolytic, anti-elastolytic, and anti-microbial effects [5,6,7,8]. Mast Cell Degranulating (MCD) peptide has a similar structure to apamin (Figure 2G) and might also act like a neurotoxin. At low concentrations, it induces mast cell degranulation; at high concentrations, it has anti-inflammatory effects.

4. Bioactivity Exerted by Bee Venom and Melittin

4.1. Anti-Inflammatory Effects

4.1.1. Anti-Inflammatory Bioactivity Targeting Various Diseases

Anti-inflammatory effects of BV and MEL targeting diverse diseases are a popular research topic. Both BV and MEL are used as therapeutic tools against diseases where inflammation is a major issue mediating morbidity, most of them being neurological or immunological disorders (Table 3). Much research is focused on BV and MEL effects on inflammatory cytokine pathways and gene expression related to inflammation and immunomodulation. Both chronic and acute diseases are subjects of anti-inflammatory action exerted by BV and MEL. Animal in vivo studies are the most common experimental design.
Despite extensive evidence supporting the anti-inflammatory and therapeutic potential of bee venom (BV) and its components like melittin, apamin, and PLA2 across diverse disease models, several research gaps remain. Most studies are limited to preclinical models, with scarce clinical trials validating safety, efficacy, dosing, and delivery mechanisms in humans. Furthermore, the mechanisms underlying BV’s immunomodulatory and anti-oxidant effects require deeper molecular investigation, especially in chronic and complex diseases. Standardization of BV extraction, formulation, and administration methods is lacking, which hinders reproducibility and clinical translation. Future research should focus on large-scale, controlled clinical trials, advanced drug delivery systems (e.g., nanoparticles, hydrogels), and long-term toxicity studies. Additionally, exploring BV’s synergistic effects with conventional therapies and its potential against antibiotic resistance and neurological disorders warrants further exploration.

4.1.2. Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a conspicuous disease target of BV (as well as its compounds) therapy (Table 4). It is a chronic inflammatory autoimmune disease that manifests as pain all over the body and may escalate into permanent loss of function, mobility issues, and a dramatic decrease in the quality of life [75]. MEL and PLA2 anti-inflammatory therapeutic effects are hot research topics of traditional medicine (especially traditional Korean medicine), and acupuncture/acupoint injection is commonly practiced with animal and human clinical models.
Most findings are limited to animal models or in silico analyses, with minimal translation into well-designed clinical trials. Delivery methods such as nanoparticles, microneedles, and liposomes are emerging but require optimization for consistent dosing, safety, and patient compliance. Future research should prioritize mechanistic studies to elucidate molecular targets, long-term safety assessments, and randomized controlled trials in humans. Moreover, integrating nanotechnology-based delivery systems with immunomodulatory strategies may enhance therapeutic outcomes in RA management.

4.1.3. Non-Disease Targeted Anti-Inflammatory Activity

Rather than targeting diseases, many researchers are looking into the potentially protective aspects of BV/melittin, which involve pathways and membrane interactions. Some are in vivo with rats and mice, but some are in vitro studies using cell lines and microorganisms (Table 5).
The immune system evolved in multicellular organisms in order to fight infections and other disorders such as cancer. By modulating immunological responses, such as T cell and macrophage activation, certain immunological pathways help to combat diseases. Both BV and melittin are known for their immunomodulatory effects due to their bioactive potential (Table 6). Nevertheless, another less abundant BV compound, PLA2, is described to exert immunomodulatory activity in BV-related studies.
Bee venom and its components, such as melittin and PLA2, show strong immunomodulatory and anti-inflammatory effects across a range of non-cancerous conditions including autoimmune, respiratory, and neurological diseases. However, several research gaps are evident. Many studies are preclinical, lacking human trials that could confirm efficacy, safety, and optimal dosing. The long-term effects of repeated BV exposure, particularly regarding immune tolerance or hypersensitivity, are not well understood. Furthermore, while novel delivery systems (e.g., nanoparticles, microneedles, LNPs) are emerging standardized methods for formulation and administration are still underdeveloped. Future research should focus on (i) well-controlled clinical studies, (ii) elucidation of mechanistic insights regarding immune regulation pathways, and (iii) the development of safe, targeted delivery platforms to minimize toxicity and maximize therapeutic outcomes.
Cancer therapy is often associated with adverse effects and might be inefficient in certain cancer types. Minimizing the side effects of chemotherapy is an active research topic that explores many alternative therapy options, such as apitherapy. Immunomodulatory effects might be considered either enhancing (immunostimulation) or suppressing (immunosuppression) [108]. Immunomodulatory agents can alter the functions of immune cells, regulate cytokine production, or affect inflammatory responses. As a result, immunomodulation has emerged as a significant therapeutic target, particularly in the treatment of cancer, autoimmune diseases, and chronic inflammation. Natural compounds and their derivatives are of interest in immunomodulation interventions [109]. Bee venom and melittin have attracted increasing attention in recent years due to their immunomodulatory properties (Table 7). These natural products might promote immune response in immunocompromised patients or control excessive immune responses by restoring immune balance, thus leading to more efficient cancer therapy.

4.2. Anti-Microbial Activity

Anti-microbial resistance (AMR) is an escalating global crisis. AMR is driven by the overuse and misuse of antibiotics, leading to the rise in healthcare-associated infections worldwide. It is projected that by 2050, 10 million people annually may die from infections that cannot be treated due to resistant bacteria and the ineffectiveness of current antibiotics [127]. In that respect, alternatives to classic antibiotics and anti-fungal agents are constantly investigated, and the use of anti-microbial peptides (AMPs) is one of them. These small molecules are abundant as part of the innate immunity in many insects, including Apis mellifera and other Apis and non-Apis types of bees [128,129]. Considering that AMPs are small amino acid chains that don’t require complex protein folding mechanisms, AMP synthesis in heterologous hosts such as bacteria or fungi is feasible, thus leading to therapeutic applications [130]. Melittin, the major protein detected in BV, is a well-studied bacterial membrane disruption agent, and it is often used as a reference in studies related to other AMPs. The anti-microbial activity of MEL and BV against diverse multidrug-resistant pathogens such as Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), and Candida albicans (C. albicans) is well studied. Numerous studies describing these results are presented in Table 8, whereas often melittin is referred to as an Anti-Microbial Peptide (AMP). Overall, the in vitro antimicrobial activity of BV and especially MEL has been sufficiently studied. However, there is scarce data regarding the anti-biofilm effect of BV and MEL, the attenuation of virulence factors of diverse pathogens, and especially the response of pathogens to BV and MEL using OMICS technologies (for example, RNA-sequencing). Future research should be focused on more preclinical studies regarding in vivo validation and therapeutic potential, as well as clinical trials to assess efficacy, feasibility, and optimal dosage.

4.3. Anti-Cancer Activity

Alternatives for cancer therapy search for the minimum side effects for the patients. The goal is to maintain the health of the non-cancerous tissue while eliminating cancerous cells; therefore, selectivity. Traditional methods of chemotherapy suffer from inducing toxic effects, aforementioned acute kidney injury, which further deteriorates the odds of patient survival. In addition, MDR (multi-drug resistance) is another reason for alternative approaches [139,213].
Cytotoxic effects and BV and melittin are directly responsible for the therapeutic potential for anti-cancer research [295,296,297,298,299,300]. As mentioned before, the anti-microbial effect of BV and melittin relies on membrane interactions and the subsequent cytotoxicity. Mammalian cancers are much more complex threats to overcome due to their resistance to follow the cell cycle, eventually cell death. By size and membrane composition, mammalian cells are different from microorganisms; therefore, a small molecule in the complexity of BV may interfere with several pathways generally overexpressed in various cancer types. With this possibility, many studies are focused on gene expression and pathways in cancers. But this exact cytotoxic potential clashes with the goal of selectivity. To reduce the cytotoxic and hemolytic activity against healthy tissue; deliveries of both BV and melittin are considered and designed extensively in obtained research articles.
The cytotoxic effect of bee venom and melittin has been shown in both human and murine cancer and a variety of cancer cells such as breast [300], hepatocellular [301], cervical [302], pancreatic [303], colorectal cancers [304], glioblastoma [88,305] and melanoma [306], and also in rat or mice animal models of cancer [125,307,308] (Table 9 and Table 10). The anti-cancer effects of bee venom and melittin are given separately.

4.3.1. Bee Venom in Cancer Research

The anti-cancer activity of bee venom (BV) has been studied in many cell lines and cancer types, alongside xenograft animal models (Table 9). The interactions of bee venom with pro-apoptotic pathways are a common study goal among these studies [256,309,310,311]. Delivery systems implementing nanoparticles are popular since BV may cause adverse effects such as unwanted hemolytic activity or allergic reactions [312,313].
Table 9. Cancer research with bee venom.
Table 9. Cancer research with bee venom.
Article NameSubstanceCancer TypeExperimental DesignAdditional Information
(G. B. Jung et al., 2018) [295]BV Breast cancerIn vitro; MDA-MB-231, PBMLs cell linesAnti-cancer effect
(A. A. Nagy et al., 2022) [296]BV Hepatocellular carcinomaIn vivo; Animal: rats
Nano delivery of BV with iron oxide
Gene Expression-Pathway
(Sevin et al., 2023) [88] BV (Apis m.)
Apamin
Melittin
PLA2
GlioblastomaIn vitro; U87MG cell line Cytotoxicity
Gene expression-pathway
Immunomodulation
(Yaacoub et al., 2022) [297]PLA2, Melittin from
BV (Apis m.)
Cervical cancerIn vitro; HeLa cell lineCytotoxicity, anti-coagulation, proteolytic activity
(M. Sharaf et al., 2024) [209]Nanoparticles loaded with apitoxin from BV (Apis m.)Hepatocellular carcinoma
Colon cancer
In vitro; HepG2, Caco-2, Vero cell lines
Nano delivery of BV by chitosan coating
Cytotoxicity
Anti-microbial
(H. N. Lim et al., 2019) [306]Melittin from BVMelanoma cancerIn vitro; B16F10, A375SM, SK-MEL-28 cell lineGene Expression-Pathway, Cell invasion inhibition
(Mansour et al., 2021) [314]BV (Apis m.) and melittinHepatocellular carcinoma In vitro; HepG2, THLE-2 cell lines
In silico; Molecular docking
Cytotoxicity,
Gene Expression-Pathway
(Małek et al., 2022) [315]BV (Apis m.)GlioblastomaIn vitro; 8-MG-BA, GAMG, HT22 cell linesNeurological, cytotoxicity,
MMP-2 and MMP-9
(Tetikoğlu & Çelik-Uzuner, 2023) [316]BV (Apis m.)Breast cancer,
Hepatocellular carcinoma
In vitro; MDA-MB-231, HepG2, NIH3T3 cell lineGenotoxicity,
Gene Expression-Pathway
(Saghi et al., 2022) [309]BV (Apis m.)Colorectal cancer In vitro; HT-29, NIH3T3 cell linesApoptosis
Gene Expression-Pathway, ROS, anti-tumor
(D.-H. Kim et al., 2020) [256]BV (Apis m.)Cervical cancerIn vitro; C33A, HeLa, Caski cell lineApoptosis, Gene Expression-Pathway
(J. Zhao et al., 2022) [310]BVPancreatic cancerIn vitro; PANC-1 cell lineApoptosis,
Cytotoxicity,
anti-metastatic
(J. E. Yu et al., 2022) [311]BVLung cancer
Glioblastoma,
Hepatocellular carcinoma
Breast cancer
In vitro; A549, A172, NCI-H460, MDA-MB-231, Hep3B cell linesApoptosis, Gene Expression-Pathway, autophagy
(Pinto et al., 2024) [32]BV (Apis m.)Hepatocellular carcinoma,
Colon cancer,
Breast cancer,
Cervical cancer,
Gastric adenocarcinoma
In vitro; HeLa, Caco-2, Vero, MCF-7, NCI-H460, AGS, PLP2, RAW 264.7, cell lines
Nanoparticle delivery of BV
Anti-inflammatory,
Therapeutic,
Cytotoxicity
(Małek et al., 2025) [317]BV (Apis m.), MelittinGlioblastomaIn vitro: MO3.1, LN229 and LN18 cell lineCytotoxicity
(Jeong et al., 2019) [318] BV (Apis m.)Lung cancerIn vitro: A549, H793, H23 lung cancer cell linesAnti-metastatic, cytotoxicity, cell invasion inhibition,
Gene expression pathway
(İlhan et al., 2025) [319]BVThyroid medullary carcinomaIn vitro: Thyroid cancer cell line
Nanoparticle delivery of BV: ZIF-8
Cytotoxicity, gene expression-pathway
(Amer et al., 2025) [320] BV (Apis m.)Lung cancerIn vitro: Vero, A549 cell line; bacteria: Mycobacterium smegmatis
Nanoparticle delivery by chitosan
Anti-bacterial
Anti-tumor
Antibiotic resistance
(Halici et al., 2025) [321]BVChronic myeloid leukemia (CML)In vitro: K562 cell lineCell viability
(Qanash et al., 2025) [322]BV (Apis m.)Hepatocellular CarcinomaIn vitro: HEPG2 cell line;
Bacteria: S. aureus, Bacillus subtilis, E. coli, Salmonella Typhimurium;
Fungi: Aspergillus niger, C. albicans
Nanoparticle delivery by zinc oxide and polyvinyl alcohol nanofilm
Anti-inflammatory, Anti-microbial, cytotoxicity Anti-oxidant activity
hemolytic activity
(Gülmez et al., 2017) [213]BV (Apis m.)Colon adenocarcinoma
Cervical cancer,
Glioblastoma
In vitro; HT-29, HeLa, C6, VeroAnti-microbial, apoptosis, apitherapy, cytotoxicity
(Abdel-Monsef et al., 2023) [215]Superoxide dismutase from BV (Apis m.)Breast cancer
Hepatocellular carcinoma
In vitro; HepG-2, MCF-7 cell linesAnti-microbial, Characterization
of BV, anti-tumor
(Sobral et al., 2016) [323]BV (Apis m.)Lung cancer
Breast cancer
Cervical cancer
Leukemia
Hepatocellular carcinoma
In vitro; HeLa, NCI-H460, RAW264.7, HepG2, MCF-7 cell linesAnti-inflammatory, cytotoxicity, Anti-oxidant activity, Characterization of BV
(El Mehdi et al., 2021) [324]BV (Apis m. intermissa)Lung cancer
Hepatocellular carcinoma
Cervical cancer
Melanoma
Breast cancer
In vitro; HeLa, NCI-H460, RAW264.7, MM127, HepG2, MCF-7 cell linesAnti-inflammatory, chemical profiling of BV,
Cytotoxicity
(Borojeni et al., 2020) [325]BV (Apis m.)Lung cancer
Cervical cancer
breast cancer
In vitro; A549, HeLa, MDA-MB-231 cell linesApoptosis, cytotoxicity
(Kabakci et al., 2023) [158]BVbreast cancerIn vitro; MCF-10A, MCF-7 cell linesApoptosis, cell cycle arrest, cytotoxicity
(Hwang et al., 2022) [36]BV (Apis m.)Lung cancerIn vitro; A549 cell lineAnti-inflammatory, cytotoxicity
(Chahla et al., 2024) [326]BV (Apis m. syriaca)GlioblastomaIn vitro; U87 cell line
In vivo; Animal: mice
Cytotoxicity, anti-tumor, brain multiform
(Abass et al., 2025) [37] BV (Apis m.)Ehrlich ascites carcinomaIn vitro: EAC cell line
In vivo; Animal: mice
Xenograft
Anti-inflammatory
Liver
(El-Bassion et al., 2016) [327]BV (honeybee)Lung Cancer
Colon Cancer
Cervical Cancer
Prostate Cancer
Larynx Cancer Rhabdomyosarcoma
Hepatocellular Carcinoma
Breast Cancer
In vitro; HeLa, A549, HCT116, PC3, HEP-2C, RDA, MCF-7, HepG2 cell lines
In vivo; Animal: rats
Cytotoxicity
(Soukhtanloo et al., 2019) [328]BV (Apis m.)Colon Cancer In vitro; HT-29, L929 cell linesApoptosis,
Gene Expression-Pathway
(Alalawy et al., 2020) [329]BV (Apis m.)Cervical Cancer In vitro; HeLa cell line
Nanoparticle delivery of BV by chitosan coating
Apoptosis, cytotoxicity
(Frangieh et al., 2019) [174]BV (Apis m.)Breast Cancer In vitro; 3T3, MCF-7 cell linesAnti-bacterial,
chemical profiling of BV, Anti-oxidant activity,
(El-Didamony, Amer et al., 2022) [330]BVProstate cancerIn vitro; OEC, PC3 cell lines
Delivery of BV
Apoptosis,
cytotoxicity,
cellular toxicity
(Duffy et al., 2020) [331]BV (Apis m.) and melittin Breast cancerIn vitro; MDA-MB-231, MCF-7, HDFa, HEK293FT, MCF-10A, MCF-12A, SKBR3 breast cancer, SUM149, SUM159, T-47D, ZR-75-1 cell linesMembrane interactions of melittin, Gene Expression-Pathway
(Duarte et al., 2022) [332]BV (Apis m.)Breast cancer
Colon Cancer
In vitro; HT-29, MCF-7 cell linesChemical profiling of BV, Synergy with 5-FU,
cytotoxicity
(Sengul et al., 2024) [333]BVLung cancerIn vitro; A549 cell lineSynergy with stem cells
(Lebel et al., 2021) [334]BV and melittinGlioblastomaIn vitro; Hs683, T98G, U737 cell linesApoptosis,
Cytotoxicity,
Characterization of BV,
anti-tumor
(M. Sarhan et al., 2020) [268]BV (Apis m.)Liver cancerIn vitro; HUh7it-1 cell lineAnti-viral, gene expression
(A. G. Kamel et al., 2024) [335]BVBreast cancer
Hepatocellular Carcinoma
In vitro; HepG2, MCF-7, HSF cell lines
Nano delivery by chitosan
Gene Expression-Pathway, anti-tumor
(Amar et al., 2021) [336]BV (Apis m.)Tongue squamous cell carcinoma
Melanoma
In vitro; TSCC, SCC25 cell linesSynergy with cisplatin, Gene Expression-Pathway, cytotoxicity
(Shaimaa H. Shadeed, 2022) [337]BVColon cancerIn vitro; Caco-2, HCT116 cell linesSynergy with cetuximab, apoptosis, Gene Expression-Pathway, cytotoxicity
(Drigla et al., 2016) [338]BVBreast cancerIn vitro; MCF-7, HS578T cell linesSynergy with propolis,
Cytotoxicity
(Khamis et al., 2024) [339]Not just BV, but also hesperidin and piperinBreast cancerIn vitro; MCF-7 cell line
In vivo; Animal: rats
Synergy with tamoxifen,
Apoptosis, Gene Expression-Pathway, anti-angiogenesis
(Badivi et al., 2024) [340]BVLung cancerIn vitro; A549 cell line
Delivery of BV by PEGylate
Apoptosis, Gene Expression-Pathway, cytotoxicity
(Mirzavi et al., 2024) [56]BVColon cancerIn vitro; C26 cell line
In vivo; Animal: mice, Xenograft
Anti-inflammatory, Gene Expression-Pathway, Anti-oxidant activity, anti-tumor
(Babayeva et al., 2024) [341]BV (Apis m.)Hepatocellular Carcinoma
Colon cancer
Ewing sarcoma
Prostate cancer
In vitro; HUH7, HT-29, Caco-2, A-673, SW-48, CARM-L12 TG3, PC-3 cell linesCytotoxicity
(Orman et al., 2025) [342]BV (Apis m.)Prostate cancer
Breast cancer
In vitro; CCD34-Lu, HEK293 MDA-MB-231, PC3Apoptosis, Delivery with mesoporous silica
Despite the increasing interest in BV as a possible anti-cancer treatment, there are still significant research gaps. Most investigations are confined to in vitro studies, with only a handful of in vivo models and no clinical trials so far, which impedes clinical application. There is a scarcity of detailed studies examining less prevalent cancers, mechanisms of drug resistance, long-term toxicity, and the comparative effects on healthy cells. Moreover, most research does not adequately address molecular mechanisms, immune modulation, or interactions within the tumor microenvironment. Although some advancements have been made with nanoparticle delivery systems, targeted and advanced delivery technologies still require further exploration. Inconsistencies regarding the source of the venom, its purification, and dosing also emphasize the need for standardization. The limited use of systems biology, bioinformatics, and personalized medicine underscores the need for stronger interdisciplinary research to fully realize bee venom’s therapeutic potential in cancer.

4.3.2. Melittin in Cancer Research

In vitro cell culture has been widely implemented in cancer research regarding melittin as well as bee venom (Table 10). Preclinical studies using animal models, in particular mouse models, are also common regarding the anti-cancer effects of melittin (Table 11). Targeting various types of cancer, many studies involve xenografts (Table 11) and the inoculation of human cancer cell lines. Xenograft is the transplantation of living tissue from a different species or species to another. In cancer research, xenograft models are powerful preclinical tools created by transplanting human tumor cells into immunocompromised animals, typically mice. These models allow researchers to observe the growth, invasion, and metastasis of human cancer cells within a living organism. They are widely used to evaluate the efficacy and toxicity of newly developed anti-cancer agents, including chemotherapy, targeted therapies, and immunotherapies. Xenograft models employing aggressive human cancer cell lines such as MDA-MB-231 are particularly valuable for studying metastatic processes [113,117]. As a result, they provide critical insights during the preclinical stage, offering a more reliable foundation for the transition to human clinical trials (Table 10).
In many of the studies, a prominent experimental design choice is melittin analogs. These peptides are engineered—through design, hybridization, synthesis, and conjugation—to reduce melittin’s drawbacks, such as cytotoxicity and hemolysis, while enhancing stability against environmental degradation and improving therapeutic efficiency. Additionally, peptide design to target specific molecular interactions is a popular research topic [155,298,343,344] (Table 10). Components of these largely chemical interactions can be other peptides, therapeutic molecules, nanoparticles such as metal ions, or other biocompatible delivery elements [301,345,346]. For melittin synthesis, plasmid-based E. coli design is a noticeable method, alongside fungi. Not just as a stand-alone, melittin can be used as an enhancer for chemotherapy agents like cisplatin. In this case, membrane disruption potential plays a major role, and melittin may have synergistic effects or may behave like a delivery tool [200,331,347,348].
Table 10. In vitro cancer models for Melittin.
Table 10. In vitro cancer models for Melittin.
Article NameCancer TypeCell LinesExperimental DesignAdditional Information
(Ebrahimdoust et al., 2023) [298]LeukemiaJurkat T, Raji cell linesMelittin-derived cecropin-A-(CM11), Melittin hybridApoptosis, Anti-tumor
(Sattayawat et al., 2025) [299]lung cancerVero, A549, NCI-H460, NCI-H1975 cell linesApis florea, Apis m.
Synergy with gefitinib
Apoptosis, Cytotoxicity
Gene expression-pathway
(Alibeigi et al., 2025) [300] Breast cancer MCF-10A, SKBR3, and MCF-7 cell linesApis cerana cerana
Melittin synthesis via E. coli
Melittin-loaded pectin
Cytotoxicity, Gene expression-pathway, Hemolytic activity, Wound healing
(S. Liu et al., 2025) [346] Cervical cancer HeLa cell line Apis m. Mel-7
Nanoparticle delivery by black phosphorous, Nanosheet
AMP, Anti-bacterial,
Wound dressing/healing
Cell viability
(Y. Li et al., 2025) [349] Cervical cancer HeLa cell line Melittin analog design
Melp5 analog
Melittin-derived: d-m159
Apoptosis
Gene expression-pathway
Oxidative stress
(Zheng et al., 2024) [301] Hepatocellular carcinoma, breast cancerHepG2, 4T1, CT26cell lineNanoparticle delivery of melittin: polydopamine
(Hamze Mostafavi et al., 2025) [122]Breast cancerBT-474
NIH3T3
Delivery
Synergy with Trastuzumab
Melittin synthesis via E. coli
Immunomodulation
(Lischer et al., 2021) [350]Breast cancerMCF-7 cell line Melittin purificationApis cerana, Anti-tumor
Cytotoxicity
(Sevin et al., 2023) [88] Brain cancer U87MG
glioblastoma cell line
BV (Apis m.)
Apamin
PLA2
Cytotoxicity, Gene expression-pathway, Immunomodulation
(Yaacoub et al., 2022) [297]Cervical CancerHeLa cell line Apis m.
PLA2
Anti-coagulation, Proteolytic activity, Cytotoxicity
(Zarrinnahad et al., 2018) [302] Cervical CancerHeLa cell line Apis mellifera
Melittin purification
Apoptosis, Honey bee venom, Hemolytic activity
Cytotoxicity
(Moghaddam et al., 2020) [351] Breast cancer4T1 cell line Cisplatin
Doxorubicin
Cytotoxicity
Gene Expression-Pathway
Hemolytic activity
(Bayat et al., 2022) [345] Breast cancerMCF-7 cell line Delivery of melittin with nanoparticles
Synergy
Cytotoxicity
(H. N. Lim et al., 2019) [306]MelanomaA375SM, SK-MEL-28, B16F10 cell linesNot just melittin Cell migration inhibition, Cell invasion, Gene expression-pathway
(Do et al., 2014) [247] Skin cancerSCC12, SCC25,
NHK cell lines
C. albicansAMP, Anti-fungal, Cytotoxicity, Skin diseases
(Y. Xiao et al., 2024) [343]Breast cancerMCF-7, SKBR3,
MDA-MB-231 cell lines
Melittin derived; Mel-22, Mel-23a, Mel-23b
Delivery of melittin
Stabilization of melittin
Serum stability
(Daniluk et al., 2022) [352]Breast cancerMDA-MB-231,
HFFF2,
MCF-7 cell lines
Delivery of melittin with nanoparticlesGene expression-pathway
(Dabbagh Moghaddam et al., 2021) [353] Breast cancer4T1 and SKBR3 cell lines Delivery of melittin with nanoparticles: Niosomes Gene expression-pathway
Hemolytic activity
Wound dressing/healing
(Jiang et al., 2019) [155] Liver cancerSMMC-7721 cell line Melittin hybrid design
Synergy with thanatin
AMP, Anti-bacterial, Hemolytic activity
(Y. Wu et al., 2017) [344] Liver cancerSMMC-7721 and
HepG2 cell lines
Melittin derived; Mel-S4, Mel-S3, Mel-S1, Mel-S2Hemolytic activity
(Sahsuvar et al., 2023) [159] Cervical cancer
Breast cancer
HeLa, 3T3,
C33A, NSF, MCF-7 cell lines
Synergy
Melittin hybrid
Conjugate
Anti-bacterial, Anti-oxidant activity, Cytotoxicity, Folic acid, Hemolytic activity
(E. Han et al., 2023) [354]Breast cancerMCF-7 cell lineDelivery of melittin
Not just melittin
Doxorubicin
Gene expression-pathway
Drug resistance
Chemotherapy
(Jamasbi et al., 2018) [162] Gastric cancerMKN-7, MKN-74, NUGC-3 cell linesMelittin synthesis via E. coliAnti-bacterial, Cytotoxicity
ROS, Hemolytic activity
(Kyung et al., 2018) [347]Lung, Breast and Cervical cancerA549, NCI-1299,
MCF-7, HeLa cell lines
Delivery of melittinApoptosis
Membrane interactions
Cell penetrating
Cytotoxicity
(M. Su et al., 2016) [355] Ovarian cancerSKOV3 cell lineMelittin-derived; atf-melittin
Melittin synthesis via fungi
Anti-tumor
Honey bee venom
(Qi et al., 2020) [356]Cervical cancerHeLa cell line Delivery of melittin with nanoparticlesApoptosis
Cytotoxicity
(Honari et al., 2024) [357] Non-small cell lung cancerA549, Calu-3, MRC-5 cell linesDelivery of melittin with nanoparticles: niosomesApoptosis
Cytotoxicity
Wound dressing/healing
(Ertilav & Nazıroğlu, 2023) [305] Glioblastoma DBTRG-05MG cell line Cisplatin Synergy Apoptosis
Anti-tumor
Cytotoxicity
Gene Expression-Pathway
Honey bee venom
Oxidant activity
(Duffy et al., 2020) [331]Triple negative breast cancerSKBR3, MDA-MB-231, MCF-10A, HEK293FT, SUM149, SUM159, MCF-12A, HDFa, T-47D, ZR-75-1, MCF-7 cell linesDelivery
BV
Bombus terrestris
Apis m.
Membrane interactions of melittin
Gene Expression-Pathway
(El-Didamony et al., 2024) [187] Colon cancer Liver cancerHCT116, Wi-38, Huh7 cell linesMelittin-derived: melittin alcalase-hydrolusate
Melittin hybrid
Characterization of BV
Anti-bacterial
Anti-biofilm
Anti-tumor
Apis m.
Cell migration inhibition
Cytotoxicity
Multifunctional bioagent
(Zamani et al., 2024) [304]Colorectal cancerHCT116 cell line Cytotoxicity
Gene Expression-Pathway
Autophagy
(Z. Jin et al., 2018) [358]Bladder cancerT24 and 5637
cell line
Gene expression-pathway
(Sangboonruang et al., 2020) [359]MelanomaNIH3T3 and A375 cell lines Apis florea
Apoptosis
Gene Expression-Pathway
Cytotoxicity
(H. Li, 2024) [360]Lung cancerH1299 and
A549 cell lines
Gene expression-pathway
Anti-angiogenesis
Anti-tumor
(Kreinest et al., 2020) [361]Hodgkin lymphomaKM-H2 and
L-428 cell lines
Cisplatin SynergyCytotoxicity
Chemotherapy resistance
(Tipgomut et al., 2018) [362]Human Bronchogenic Carcinoma
Lung cancer
ChaGo-K1, THP-1 Wi-38 cell lines Apoptosis
Cell cycle arrest
Cytotoxicity
Apis m.
(X. Li et al., 2022) [363] Lung cancerA549 cell line Apoptosis
Ferroptosis
Wound dressing/healing
ROS
(Kong et al., 2016) [364] Gastric cancerSGC-7901 Cell line Apoptosis
ROS
Gene Expression-Pathway
(Zorilă et al., 2020) [348] Colon cancer
Osteosarcoma
Liver cancer
HT-29, MG-63, HepG2, L929 cell linesLiposome
In silico analysis
AMP
Membrane interactions
(Q. Chen et al., 2019) [365]Liver cancerHuh7, SMMC-7721 and HepG2 cell lines Gene expression-pathway
(J. Yao et al., 2020) [366] Bladder cancer5637 and UM-UC-3 cell lines Anti-metastatic
Cell migration inhibition
Gene Expression-Pathway
(Mir Hassani et al., 2021) [367]Breast cancerMDA-MB-231 cell line Anti-angiogenesis
Anti-tumor
Gene Expression-Pathway
(X. Wang et al., 2017) [303] Pancreatic cancerSW1990, Capan1, AsPC-1, BXPC-3 and HEK293T
cell lines
Gemcitabine SynergyChemotherapy resistance
Anti-tumor
Gene Expression-Pathway
(X. Li et al., 2023) [368] Lung cancerA549 cell line Anti-tumor, Autophagy
Apoptosis, Gene Expression-Pathway
(Salimian et al., 2022) [369] Breast cancerMDA-MB-231 cell line Anti-metastatic, Cell migration inhibition, Cytotoxicity, Gene Expression-Pathway
(Z. Zhang et al., 2016) [370] Human hepatocellular carcinomaBel-7402, Hep3b, Huh7, HUVEC, HepG2, LO2, SMMC-7721, MHCC97-H cell lines Anti-angiogenesis
Anti-metastatic
Apis m.
Gene Expression-Pathway
(Jeong et al., 2014) [371] Breast cancerMDA-MB-231 and MCF-7 cell linesApis m.Cell invasion
Gene Expression-Pathway
(J.-Y. Huang et al., 2021) [372] Gastric adenocarcinomaAGS cell line Anti-metastatic
Gene Expression-Pathway
Wound dressing/healing
(Y. Lv et al., 2022) [373] Breast cancer
Hepatocellular carcinoma
MCF-7,
Hepa1-6
cell lines
Melittin analog
Melittin synthesis
In silico analysis
Apis m.
Anti-tumor
Cytotoxicity
Hemolytic activity
Molecular dynamics
(H. Jung et al., 2022) [312] Cervical cancerBEAS-2B, RAW264.7, RBL-2H3, HeLa
cell lines
Melittin derived Anti-inflammatory
Allergy
Anti-oxidant activity
Cytotoxicity
(Plasay et al., 2022) [374] Breast cancerMCF-7 cell line Apoptosis
Gene Expression-Pathway
(Ceremuga et al., 2020) [375] ALL, CMLCCRF-CEM, K-562 cell lines Apis m.Apoptosis
(Plasay & Muslimin, 2024) [376]Colorectal cancerWiDr cell line Gene expression-pathway
Cytotoxicity
Honey bee venom
(Obeidat et al., 2023) [377]LeukemiaK-562 cell line BV
Melittin purification
Apoptosis
Cell cycle arrest
Apis m.
Cytotoxicity
(Alonezi et al., 2017) [378] Ovarian cancerA2780, A2780CR cell linesSynergy with cisplatin
Delivery of melittin
Activity/mechanism
Cytotoxicity
(Lebel et al., 2021) [334]GlioblastomaHs683, U737, T98G cell lines Characterization of BV
BV
Apoptosis
Anti-tumor Cytotoxicity
Li et al., 2018 [307] Lung cancer
Cervical cancer
A549 and HeLa cell linesDelivery by nanoparticles: zeolitic imidazolateGene expression-pathway
(Wattanakul et al., 2019) [379]Colon cancerCaco-2 cell line Delivery of melittin with nanoparticles: alginateChemotherapy enhancement
(H. Lai et al., 2017) [380] Breast cancerMCF-7 Cell lineDelivery of melittin with nanoparticles: nanodiamondsCytotoxicity
(Nikodijević et al., 2024) [381]Colon cancerHT-29 and MRC-5 cell lines Apoptosis
Drug resistance
Cytotoxicity
(M. C. Shin et al., 2016) [382] Glioblastoma
Cervical cancer
U87MG, LS174T, MDCK, CT26 and
HeLa cell lines
Gelonin synergy
Characterization
Melittin
Genetic design
Anti-tumor
Cytotoxicity
Ribosome inhibition
(Maani et al., 2023) [383] In silico analysis Melittin hybrid design
In silico analysis
Molecular dynamics of melittin
(Keykanlu et al., 2016) [384]Breast cancerMCF-7 cell line Delivery of melittin with nanoparticles: Perfluorooctyl Bromide
Synergy with lactoferrin
Hemolytic activity
(S.-K. Zhang et al., 2016) [200] Glioblastoma
Cervical cancer
HeLa cell line Apis m.
Melittin-derived peptide: AR-23, RV-23
AMP
Anti-bacterial
Hemolytic activity
Membrane interactions
(Keil et al., 2020) [55] Lung cancerJurkat T lymphocytes, A549 cell lines Melittin is only reference moleculeAnti-inflammatory
Immunomodulation
Asthma disease
Endosomal escape
(Rajabnejad et al., 2018) [385] Lung cancerL929 and A549 cell lines Apis m.
Delivery of melittin with AS1411
Alpha helical peptide
Cytotoxicity
Hemolytic activity
(C. Zhou et al., 2020) [386] Esophageal carcinomaTE1 and Het-1a cell lines SynergyApoptosis
Anti-tumor
Cell migration inhibition
Cell cycle arrest
Gene Expression-Pathway
ROS
(Soliman et al., 2019) [387] Gastric adenocarcinomaCOLO205, HCT-15, AGS cell lines MelittinMembrane Interactions Cytotoxicity
(Nakagawa et al., 2020) [388] MelanomaA375, A2058 cell lines Allium sativum
Melittin is the only reference
Cytotoxicity
Hemolytic activity
(Gao et al., 2024) [389] Lung cancer A549 cell lineMelittin hybrid: melittin-mil-2 Anti-tumor
Gene Expression-Pathway
(Erkoc et al., 2022) [57] Breast cancerHUVEC, MDA-MB-231, HEK293T, RAW264.7 and
HMEC-1 cell lines
BV
BV elements
melittin derived
Anti-inflammatory
Honeybee
Gene Expression-Pathway
Apis m.
Anti-tumor
(Delvaux & Rice, 2022) [390] Liver cancerHepG2 cell line Melittin derived; melP5
Melittin synthesis
Conjugate
Delivery of melittin
Endosomal escape with melittin
(Yan et al., 2022) [391] Bladder cancerT24, EJ, BIU87
SV-HUC-1 cell lines
Delivery of melittin
RNA
Apoptosis
Gene Expression-Pathway
Anti-tumor
(Daniluk et al., 2019) [392] Breast cancerMDA-MB-231
and MCF-7 cell lines
Delivery of melittin with nanoparticles: grapheneApoptosis, ROS, Cytotoxicity, Membrane interactions
(R. Wang et al., 2022) [393] CancerIn silico analysisAMP
Melittin derived
Membrane interactions
(Hussein et al., 2023) [394]Breast cancerMDA-MB-231, MCF-7 cell linesDelivery of melittin Carnosine
Synergy with olaparib
(Gasanoff et al., 2021) [124] T cell leukemiaJurkat T cell lineDockingMembrane interactions
Immunomodulation
(Q. Liu et al., 2025) [395] Hepatocelular carcinoma293T, A20, COC1, Hepa1-6, Hepg2, Huvec, U937MelittinMembrane interactions
Peptide design
Hemolytic activity
(Raveendran et al., 2020) [396] Breast Cancer MDA-MB-231
and MCF-7 cell lines
Delivery of melittinCytotoxicity
(R. Wu et al., 2025) [397] Ovarian cancer SKOV3 cell lineMelittinApoptosis
Gene Expression-Pathway
Cell cycle arrest
(Feng et al., 2020) [398] Colon CancerCT26 cell lineDelivery of melittin
Hydrogel
Membrane interactions
(Motiei et al., 2021) [399]Breast Cancer MDA-MB-231 cell lineDelivery of melittin with nanoparticles: chitosan Apoptosis
Nano peptide: LTX-315
Synergy with miRNA34a
(Ibrahim et al., 2025) [400] Lung cancerA549 cell line Gene Expression-Pathway
Synergy
(Bahreyni et al., 2023) [110]Breast and cervical cancer, melanoma4T1, B16F10, HeLa, MDA-MB-231 cell linesSynergy
Delivery
Anti-tumor
Melittin derived
Immunomodulation
Table 11. In vivo animal model cancer research with melittin (cell lines used for induction of in vivo cancer models).
Table 11. In vivo animal model cancer research with melittin (cell lines used for induction of in vivo cancer models).
Article NameCancer TypeCell LinesExperimental DesignAdditional Information
(H. Wang et al., 2025) [111]Breast cancer4T1 cell lineDelivery of melittin
Conjugate
Melittin synthesis
Xenograft
Cytotoxicity
Anti-tumor
Immunomodulation
Promelittin
(Song et al., 2023) [112]Cervical cancer
Melanoma
HeLa, B16F10-OVA, DC2.4-Gal8-GFP cell linesVaccine
D-melittin
Drug delivery
Immunogenicity
Immunomodulation
Cell viability
(Rocha et al., 2022) [401]Bone cancer
Colorectal cancer
HT-29 cell lineXenograft Apis m.
Anti-metastatic
Cell viability
(S. Jia et al., 2025) [402]OsteosarcomaK7M2 cells and BMDCsAnimal: mice
Melittin-derived peptide
AMP
Hemolytic activity
(H. Zhang et al., 2025) [403]GlioblastomaHs683 and T98G cell lines Delivery of melittin with nanoparticles: liposome
Xenograft
Synergy with Resveratrol
Anti-tumor
Hemolytic activity
Gene Expression-Pathway Hemolytic activity
(F. Jia et al., 2021) [404]Non-small cell lung carcinoma,
Ovarian cancer
NCI-H358 and SKOV3 cell linesDelivery of melittin
Xenograft
Anti-tumor
Cytotoxicity
Hemolytic activity
(S. Lv et al., 2021) [405]Breast cancer
Lung cancer
Colon carcinoma
A549, CT26, 3T3, MDA-MB-231 cell linesDelivery of melittin with nanoparticles
D-melittin
Anti-tumor
Hemolytic activity
(Shir et al., 2011) [113]Glioblastoma,
Breast cancer,
Vulval epidermoid carcinoma
A431, U138MG, U87MG, MDA-MB-231 cell linesDelivery of melittin
Xenograft
Gene Expression-Pathway Interactions
Hemolytic activity
Immunomodulation
(S. Kim et al., 2022) [406]Breast cancer
Acute Monocytic Leukemia
4T1 and THP-1 cell lines Delivery of melittin
Hybrid design
Xenograft
Anti-metastatic
Honeybee
Hemolytic activity
(X. Kang et al., 2024) [169] Hepatocellular carcinomaHepG2 cell line E. coli, K. pneumoniae, S. aureus
Not just melittin
Anti-bacterial
AMP
Bacterial vaginosis disease
Cytotoxicity
(Y. Wang et al., 2025) [407]Lung cancer A549 lung cancer cell line (A549/DDP) Xenograft Gene Expression-Pathway
Chemotherapy resistance
Honeybee
(J. Zhang et al., 2023) [408]Hepatocellular carcinomaBHK-21, L02, epG2 cell lines
Delivery of melittin with nanoparticles
Xenograft
Cytotoxicity
Membrane interactions
Hemolytic activity
(X. Yu et al., 2019) [114]Liver cancer,
Colon carcinoma,
Melanoma,
Breast cancer
4T1, B16F10, CT26 cell lines Delivery of melittin with nanoparticles
Xenograft
Gene Expression-Pathway
Anti-metastatic
Anti-tumor
Immunomodulation
(Chang et al., 2022) [409]Breast cancerMCF-7 and 4T1 cell linesMelittin synergy with radiation
Xenograft
Apoptosis
Apis m.
Anti-tumor
(P. Wu et al., 2022) [115]Breast cancer,
Hepatocellular carcinoma
4T1 and HEP1-6 cell lines Not just melittin
Delivery of melittin with siRNA nanoparticles
Synergy
Xenograft
Anti-metastatic
Anti-tumor
Cold tumor
Immunomodulation
Apoptosis
Pathway interactions
(P. Xu et al., 2024) [410]GlioblastomaU251 cell lineXenograftGene Expression-Pathway
Cell cycle arrest
Anti-metastatic
Anti-tumor
(Meng et al., 2024) [411] Hepatocellular carcinoma,
Cervical cancer,
Leukemia,
HeLa, Huh7, HEK293T,
K-562, HEK293, HepG2, Hepa1-6 cell lines
Delivery of vector
Melittin analog design: p5RHH
Transduction
Transfection
(S.-F. Zhang & Chen, 2017) [412] Lung cancerA549 cell lineXenograftGene Expression-Pathway
Cell migration inhibition
Apis m.
Wound dressing/healing
Anti-angiogenesis
Anti-tumor
(S. Zhang et al., 2021) [413]Lung cancerA549 cell lineXenograftApoptosis
Gene Expression-Pathway
Chemotherapy resistance
Anti-tumor
Glycolysis inhibition
(H. Zhu et al., 2021) [414]Bone cancer143 B cell lineXenograftGene Expression-Pathway
Anti-metastatic
(Qin et al., 2016) [415]Bone cancerUMR-106 cell lineXenograftAnti-tumor
Anti-angiogenesis
Gene Expression-Pathway
(Yan et al., 2023) [416]Prostate CancerDU145, PC3 cell linesSynergy with cisplatin
Xenograft
Wound dressing/healing
Gene Expression-Pathway
Cell migration inhibition
Anti-tumor
Cisplatin sensitivity
(R. Yu et al., 2021) [417]Lung cancerA549 and H358 cell linesXenograftApoptosis
Gene Expression-Pathway
Cytotoxicity
Cell migration inhibition
(C. Lee et al., 2017) [116]Lung cancer
Papillary adenocarcinoma
LCC, MLE12, and
H441 cell lines
XenograftGene Expression-Pathway
Anti-tumor
ROS
Immunomodulation
(Luo et al., 2023) [418]Colorectal cancerHCT116, HT-29, SW-480, CCD 841 cell linesXenograftApoptosis
Anti-tumor
(X. Wang et al., 2018) [419]Pancreatic cancerPANC-1, SW1990, HPDE, PATU8988, HS766T and BCPC3 cell linesRNA
Xenograft
Gene Expression-Pathway
(X. Yu et al., 2020) [420]MelanomaB16F10 and
E0771 cell lines
Delivery of melittin with nanoparticles
Xenograft
Anti-tumor
(M. Liu et al., 2016) [117] Lung cancer
Liver cancer Breast cancer Ovarian cancer
A549, SMMC-7721, MDA-MB-231, SKOV3 and
CTLL-2 cell lines
Melittin fusion design
Xenograft
Anti-tumor
Cytotoxicity
Immunomodulation
(Guo et al., 2023) [118]Breast cancer4T1 cell lineDelivery of melittin with nanoparticles: metal-phenol
Xenograft
Anti-tumor
Hemolytic activity
(Cheng & Xu, 2020) [421] Breast cancer Colon cancerMCF-7, HCT116
cell lines
Delivery of melittin with nanoparticles: Melittin synthesis design
Xenograft
Redox sensitivity
(Q. Zhao et al., 2022) [422]Anaplastic thyroid carcinomaCAL-62 and C-643 cell lines Synergy with apatinib
Xenograft
Gene Expression-Pathway
Pyroptosis
Anti-tumor
(Y. Xie et al., 2023) [423]Liver cancerHuh7 and HEK293 cell linesDelivery of melittin-derived peptide
(I.-H. Han et al., 2022) [121]MelanomaB16F10 and
THP-1 cell lines
XenograftAnti-tumor
Gene Expression-Pathway
Immunomodulation
Wound dressing/healing
(Khorsand-Dehkordi & Doosti, 2024) [313]Breast cancerMCF-7, MCF-10A, RAW264.7 and
4T1 cell lines
Melittin synthesis via E. coli
Xenograft
Anti-tumor apoptosis
Gene Expression-Pathway Hemolytic activity
(Rahman et al., 2025) [424] Ovarian cancerHEK293, KGN, OVCAR-3, SKOV3 cell linesAnimal: mice
Xenograft
Gene Expression-Pathway
(Sun et al., 2025) [425] Ovarian cancerSKOV3 cell linesAnimal: mice
İnjection
Xenograft
Gene Expression-Pathway
(Pedro et al., 2025) [426] OsteosarcomaMG-63, UMR-106, D-17 cell lines3D cell culture Cytotoxicity
Cell migration inhibition
(X. Xie et al., 2022) [427] Osteosarcoma143 B cell lineAnimal: mice
Xenograft
Apoptosis
Gene Expression-Pathway
(Y. Li et al., 2018) [307] Cervical cancer Lung cancerA549, HeLa, U14 cell linesAnimal: mice
Xenograft
Gene Expression-Pathway
Anti-tumor
Hemolytic activity
Nanodelivery with zeolitic imidazole
(D. Zhang et al., 2025) [126] Breast cancer4T1Animal: mice
Injection
Delivery of melittin with nanoparticles: hyaluronic acid (HA) and metal (Fe)
Anti-tumor
ROS
Anti-oxidant activity
(Dai et al., 2025) [125]Breast Cancer Animal: mice
Delivery of melittin
Gene Expression-Pathway
(Tang et al., 2022) [119] MelittinB16F10, B16, MB-49, MC38, MC38-OVAAnimal: mice
Delivery with MnO2
Vaccine
Anti-tumor
Cytotoxicity
Immunomodulation
(K. Yang et al., 2023) [120] MelittinB16-luc, B16F10 Animal: mice
Vaccine
Delivery with hydrogel
Anti-tumor
Cytotoxicity
Hemolytic activity
Immunomodulation
(Shen et al., 2024) [123] MelittinCT26, NIH3T3, HUVEC, CAF Animal: mice
Delivery
Synergy
Hemolytic activity
Immunomodulation
Although melittin has been more extensively studied in vivo than bee venom, several notable limitations on melittin research become apparent. Most in vitro studies focus on common cancers like breast, cervical, and lung, while aggressive types such as pancreatic, esophageal, and blood cancers remain underexplored. Research often relies on a few standard cell lines (e.g., HeLa, MCF-7, A549, 4T1), limiting model diversity. Although nanoparticle delivery systems and melittin analogs are being developed, variability in venom sources, delivery methods, and design strategies hinders standardization. In vivo studies are few, mainly in mouse xenografts, with little progress toward clinical trials. Moreover, while cytotoxicity and apoptosis are well studied, interactions with the tumor microenvironment, immune response, metastasis, and chemotherapy resistance are less understood. Additionally, multi-omics or systems are deficient biology approaches that could illuminate the comprehensive biological effects. Lastly, long-term animal studies inadequately address the toxicity and off-target consequences—particularly hemolytic activity. Closing these gaps is vital for advancing melittin from experimental treatment to clinical use in cancer care.
In light of the identified research gaps in both in vitro and in vivo investigations, future studies exploring melittin and bee venom for cancer treatment should focus on several important areas. To enhance the therapeutic significance of melittin, it is crucial to broaden the range of cancer models, particularly by including rare, treatment-resistant, and metastatic forms. Additionally, future research should aim to diversify the cell lines used and implement 3D cultures or organoid systems that more accurately represent the tumor microenvironment. In vivo investigations should advance beyond simplistic xenograft models to encompass metastatic and immunocompetent systems, allowing for a more accurate assessment of effectiveness, toxicity, and immune reactions. Standardized melittin analogs and delivery systems are needed to reduce hemolysis and improve tumor selectivity. Applying multi-omics and systems biology approaches may uncover mechanisms, resistance pathways, and biomarkers for therapy monitoring. Studies exploring the combination of melittin with current chemotherapeutics, immunotherapies, or radiotherapies should be expanded through well-planned synergy assessments, along with thorough long-term safety investigations. Ultimately, it will be essential to address the translational gap with comprehensive preclinical toxicology, pharmacokinetics, and clinical trial frameworks to propel melittin-based therapies toward practical oncology use.

5. Anti-Oxidant Activity

Anti-oxidant activity refers to the capacity of a substance to neutralize free radicals (harmful molecules such as Reactive Oxygen Species, ROS). Free radicals can cause oxidative stress in cells, damaging DNA, proteins, and lipids [162]. This contributes to the development of many diseases, such as aging, cancer, cardiovascular disease, and neurodegenerative disorders.
Bee venom and its main component, melittin, are not only notable for their anti-inflammatory, anti-microbial and anti-cancer effects, but also for their anti-oxidant activity (Table 12). Melittin has the potential to neutralize free radicals and reduce cellular damage associated with oxidative stress. Therefore, bee venom and melittin are considered protective or supportive agents in diseases where oxidative stress plays a key role.

6. Conclusions

This scoping review aims to comprehensively update the current research on the therapeutic potential and bioactivity of bee venom (BV) and its major protein melittin (MEL), which could be systematically (meta)analyzed in future work. It highlights the research fields where BV, MEL and other compounds were predominantly studied while at the same time identifying research gaps and fields that have received comparatively less attention. Figure 3 shows the growing publication numbers on bee venom (BV) and melittin (M), particularly regarding their anti-microbial (overall 179 studies) and anti-cancer (overall 170 studies) effects, followed by anti-inflammatory (overall 85), immunomodulatory (overall 37), and anti-oxidant (overall 32) properties (Figure 3A). Publication trends reveal a sharp increase since 2020, peaking in 2022 (68 studies) and remaining high through 2025 (62 studies so far) (Figure 3B), highlighting sustained scientific attention to their therapeutic potential.
The literature is largely relevant to anti-cancer and anti-microbial activities. The main reason for that is that cancer and infectious diseases are among the major public health issues worldwide. Another reason is the availability of numerous in vitro protocols, thus making it relatively easy to conduct anti-cancer and anti-microbial studies. Anti-cancer research commonly emphasizes the detection of apoptosis-related markers in vitro, anti-metastatic effects, and synergy with conventional chemotherapeutic agents (Table 9 and Table 10). In vivo studies are less frequent and are predominantly conducted using pure melittin rather than bee venom (Table 11). E. coli, S. aureus, and C. albicans are the most studied micro-organisms, and drug/antibiotic resistance is the most popular area for BV/melittin anti-microbial research (Table 8). After the COVID-19 pandemic in 2020, not surprisingly, studies on the effects of BV/melittin against SARS-CoV-2 and MERS viruses have increased.
The anti-inflammatory effects of BV and MEL on rheumatoid arthritis have been extensively studied using animal models (Table 3, Table 4 and Table 5). However, research on their effects on Parkinson’s and Alzheimer’s diseases remains limited. Although these neurodegenerative disorders are associated with inflammation, the required experimental models are technically challenging and relatively costly. Inflammatory conditions are closely linked to immunological deficiencies, which need to be addressed through immunomodulatory approaches. The immunomodulatory activity of BV/MEL has been relatively less studied (Table 6), and most of the existing research focuses on the effects of MEL in cancer models (Table 7). This suggests that anti-cancer studies involving BV/MEL extend beyond cancer treatment alone, also contributing to our understanding of their immunomodulatory potential.
Studies on anti-oxidant activity of BV and/or melittin include a broad spectrum of in vivo (ducks, mice, rats, fish, quail) and in vitro (cell lines such as MCF-7, HeLa, Raw264.7, HT22, and others) models, targeting diseases including neurodegenerative and inflammatory diseases, cancer, diabetes, and colitis. Many studies report anti-oxidant effects alongside anti-inflammatory, cytotoxic, and immunomodulatory, often through gene expression analysis, DPPH assays, or in synergy with other agents (e.g., L-DOPA, cordycepin, propolis, Cu2+) (Table 12). BV is delivered through various systems, including injection, microneedles, nanoparticles, and acupuncture, reflecting growing interest in targeted or alternative therapies. Additionally, multiple studies investigated the chemical profile and hemolytic activity of BV, underlining its complex bioactivity and potential for both therapeutic interventions and toxicity.
Clinically, BV and MEL show promise as adjunctive or alternative therapeutic agents, particularly in conditions where conventional treatments are limited. Their strong anti-bacterial and anti-inflammatory activities point to possible applications in wound healing, drug-resistant infections, and chronic inflammatory diseases. In oncology, MEL pro-apoptotic and cytotoxic properties can be used in targeted delivery systems to minimize systemic toxicity while treating aggressive or resistant tumors. Melittin appears more advantageous in clinical trials than bee venom, as it is a peptide, suggesting that it can be produced synthetically under strict laboratory conditions without the need for beekeeping. On the other hand, bee venom is a mixture of numerous compounds that might act synergistically.
In the current body of research, in vivo studies are predominantly related to investigations of anti-inflammatory, anti-oxidant, and immunomodulatory effects implementing organism-level models necessary to reveal systemic immune interactions across multiple tissues and organs (Table 13). In contrast, cancer research relies largely on in vitro approaches, implementing well-characterized cell lines, the relative simplicity of modeling single-tissue pathologies, and reduced infrastructure requirements. Nevertheless, clinical studies remain limited due to ethical, logistical, and technical constraints. Anti-microbial investigations may be conducted either in vitro or in vivo, because microorganisms are simple unicellular organisms (Table 13). Furthermore, melittin is more frequently investigated in cancer-related studies than bee venom (BV), given that BV composition varies depending on species and collection methods, whereas melittin, as its principal component, is commercially available in standardized form of a well-defined chemical structure.
Conclusively, bee venom and its major compound, melittin, are among the most promising natural compounds due to their diverse biological activities. Their well-documented anti-inflammatory, anti-microbial, immunomodulatory, anti-cancer, and anti-oxidant properties suggest potential applications in the prevention and treatment of various diseases. Melittin’s ability to modulate cellular signaling pathways to suppress inflammation, regulate immune responses, combat microbial agents, reduce oxidative stress, and inhibit the proliferation and spread of cancer cells highlights its significant pharmacological value. These multifaceted effects underscore the need for continued research on bee venom and melittin, as well as further evaluation in clinical trials.

Author Contributions

Conceptualization, D.M.; Methodology, P.M.E. and D.M.; Resources, P.M.E. and D.M.; Writing—Original Draft Preparation, P.M.E., F.B.-T. and S.Ç.-U.; Writing—Review & Editing, P.M.E., F.B.-T., S.Ç.-U., S.K., O.Y. and D.M.; Supervision, D.M., S.K. and O.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

P.M.E. is a student at Karadeniz Technical University and received an ERASMUS+ internship at the University of Thessaly, Department of Biochemistry & Biotechnology (Larissa, Greece).

Conflicts of Interest

Author Oktay Yıldız was employed by Okta R&D Eng Services Industry Trade Limited Company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Figure 1. PRISMA flowchart: Implementation of PRISMA guidelines followed during this review in order to include eligible studies [16].
Figure 1. PRISMA flowchart: Implementation of PRISMA guidelines followed during this review in order to include eligible studies [16].
Molecules 30 04003 g001
Figure 2. Chemical structure of major bee venom compounds: (AG) show the secondary and 3D structures of melittin, apamin, tertiapin, phospholipase A2, hyaluronidase, secapin, and mast cell degranulation peptide, respectively. (AE) Domain organization, sequence conservation, and predicted physicochemical features of principal bee venom proteins visualized using bioinformatics tools. (A) Melittin, a 26-amino-acid amphipathic peptide responsible for hemolytic and cytolytic activities, shows a characteristic α-helical conformation. (B) Apamin, a small neurotoxic peptide that blocks Ca2+-activated K+ channels, displays a compact disulfide-stabilized α-helical structure. (C) Tertiapin, known for its potassium channel inhibitory activity, presents a short α-helix with disulfide bridges. (D) Phospholipase A2 (PLA2), the primary enzymatic component of bee venom, possesses conserved catalytic and Ca2+-binding domains, which contribute to membrane degradation and inflammation. (E) Hyaluronidase, often termed the “spreading factor,” shows conserved glycosidic hydrolase motifs and facilitates venom diffusion through connective tissues. (F,G) Three-dimensional molecular structures of smaller venom-derived peptides, including Secapin (F) and the Mast Cell Degranulating (MCD) peptide (G), highlight the presence of loop and β-turn motifs important for their antimicrobial and immunomodulatory activities. Structural models were generated using protein databases and homology modeling algorithms to visualize functional domains and peptide folding patterns (obtained from pubchem.ncbi.nlm.nih.gov and www.rcsb.org databases).
Figure 2. Chemical structure of major bee venom compounds: (AG) show the secondary and 3D structures of melittin, apamin, tertiapin, phospholipase A2, hyaluronidase, secapin, and mast cell degranulation peptide, respectively. (AE) Domain organization, sequence conservation, and predicted physicochemical features of principal bee venom proteins visualized using bioinformatics tools. (A) Melittin, a 26-amino-acid amphipathic peptide responsible for hemolytic and cytolytic activities, shows a characteristic α-helical conformation. (B) Apamin, a small neurotoxic peptide that blocks Ca2+-activated K+ channels, displays a compact disulfide-stabilized α-helical structure. (C) Tertiapin, known for its potassium channel inhibitory activity, presents a short α-helix with disulfide bridges. (D) Phospholipase A2 (PLA2), the primary enzymatic component of bee venom, possesses conserved catalytic and Ca2+-binding domains, which contribute to membrane degradation and inflammation. (E) Hyaluronidase, often termed the “spreading factor,” shows conserved glycosidic hydrolase motifs and facilitates venom diffusion through connective tissues. (F,G) Three-dimensional molecular structures of smaller venom-derived peptides, including Secapin (F) and the Mast Cell Degranulating (MCD) peptide (G), highlight the presence of loop and β-turn motifs important for their antimicrobial and immunomodulatory activities. Structural models were generated using protein databases and homology modeling algorithms to visualize functional domains and peptide folding patterns (obtained from pubchem.ncbi.nlm.nih.gov and www.rcsb.org databases).
Molecules 30 04003 g002
Figure 3. (A) The number of studies related to specific bee venom (BV)/melittin (M) bioactivity; (B) The overall number of relevant studies published between 2010–2025.
Figure 3. (A) The number of studies related to specific bee venom (BV)/melittin (M) bioactivity; (B) The overall number of relevant studies published between 2010–2025.
Molecules 30 04003 g003
Table 1. Major compounds detected in bee venom [4,6,11,15].
Table 1. Major compounds detected in bee venom [4,6,11,15].
Type of Bee Venom ElementsBee Venom Elements
EnzymesPhospholipase A2 (PLA2), phospholipase B (PLB), hyaluronidase, phosphatase, and α-glucosidase
PeptidesMelittin, apamin, mast cell degranulating (MCD) peptide, adolapin, tertiapin, secapin, melittin F, cardiopep, procamine, minimine
Other moleculesPhospholipids, histamine, dopamine, noradrenaline, c-aminobutyric acid, a-amino acids, glucose, fructose, pheromones, isopentyl acetate, isopentanol, n-butyl acetate, n-hexyl acetate, 2-nonanol, n-octyl acetate, n-decyl acetate, benzyl alcohol, benzyl acetate, Ca, Mg, P, and lipids
Table 2. The search terms for the databases.
Table 2. The search terms for the databases.
Stand-Alone Search TermsAdditional Terms for Combinations
General TermsSuggested Terms
Bee VenomAnti-bacterial, anti-fungal, anti-microbial, anti-viral, bioactivity, anti-cancer, phospholipase, therapyBiofilm, fungus, hyaluronidase
MelittinAnti-bacterial, anti-fungal, anti-microbial, anti-viral, bioactivity, cancerCell, immunogenicity, signal
Table 3. Anti-inflammatory bioactivity exerted by BV/MEL on targeted diseases/disorders.
Table 3. Anti-inflammatory bioactivity exerted by BV/MEL on targeted diseases/disorders.
Article Substance and SourceDiseaseExperimental DesignAdditional Information
(Ahmedy et al., 2020) [17]Melittin
(Apis m.)
Acetic acid-induced ulcerative colitisAnimal: mice
Injection
Anti-oxidant activity
Chronic disease
Gene Expression-Pathway
(Y. M. Lee et al., 2020) [18]Apamin
(Apis m.)
Gouty ArthritisRAW264.7 cell line, mouse macrophage-like cellGene Expression-Pathway
(Z. Li et al., 2025) [19]Melittin (bee)Heat stress-induced İmmune organ damageAnimal: duck
Feeding
Gene Expression-Pathway
(Abd El-Hameed et al., 2021) [20]BV (Apis m.)EpilepsyAcupuncture
Animal: rats
Neurological
(Zahran et al., 2021) [21]BV (Apis m.)Cardiac dysfunction due to type 2 diabetesAnimal: rats
Injection
(Abdelrahaman et al., 2025) [22]BV (Apis m.)Gentamicin-induced kidney injuryAnimal: rats
Injection
Anti-oxidant Activity
Gene Expression-Pathway
Lipid peroxidation
(Aly et al., 2023) [23]BV (Apis m.)EpilepsyAcupuncture
Animal: rats
Anti-oxidant activity
Neurological
(Gu et al., 2022) [24]BV (Apis m.)
Melittin
Acne vulgarisAnimal: rats
Injection, SZ95 cell line
Bacteria: Cutibacterium sp.
Inactivation of Akt/mTOR/SREBP Signaling Pathway
(Goo et al., 2021) [25]BV (bee)Gouty ArthritisAcupuncture
Animal model: rats
(Badawi et al., 2020) [26]BV (Apis m.)Parkinson’s diseaseAnimal: mice
Injection
Anti-oxidant activity
Neurological
Synergy with L-dopa
(H. Kim et al., 2020) [27]Melittin (bee)Cisplatin-induced acute kidney injuryAnimal model: miceGene Expression-Pathway
Immunomodulation
(D. Shin et al., 2018) [28]PLA2 (bee)Atopic dermatitis
Animal: mice
Topical administration
Gene Expression-Pathway Interactions
(G.-H. Kang et al., 2020) [29]PLA2 (bee)AtheroclerosisAnimal: miceImmunomodulation
(Baek et al., 2020) [30]PLA2 (Apis m.)Alzheimer’s diseaseAnimal: miceApoptosis
Neurological
Immunomodulation
(D.-W. Kang et al., 2021) [31] BV (Apis m.)Burn injury, painAnimal: mice
Injection
Anti-nociception
Neurological
(Pinto et al., 2024) [32]BV (Apis m.)Breast, lung, gastric adenocarcinoma, cervical and colon cancerHeLa, Caco-2, AGS, NCI-H460, PLP2, MCF-7, HaCaT, HFF-1 cell linesBV production
Delivery of BV with nanoparticles: niosome
(Danesh-Seta et al., 2021) [33]Apamin (Apis)Multiple sclerosisAnimal: miceNeurological
(W.-H. Kim et al., 2017) [34] Melittin
(Apis m.)
Atopic dermatitisAnimal: mice
HaCaT cell line
Gene Expression-Pathway
Adverse Effects
(Shaik et al., 2023) [35]Melittin (honeybee)Diabetes mellitusAnimal: rats
Injection
Anti-oxidant activity
Synergy with Cordycepin
Pro-angiogenetic
Delivery with a nanoparticle
(Hwang et al., 2022) [36]BV (Apis m.)Lung CancerA549 cell lineSweet bee venom
(Abass et al., 2025) [37]BV (Apis m.)Ehrlich ascites carcinomaEAC cell line
Animal: mice
Xenograft
Liver
(Hegazi et al., 2023) [38]BV (bee)Chronic Neck PainAcupuncture
Clinical Study
Adverse effects
Anti-oxidant activity
Hemolytic activity
(Yaghoubi et al., 2022) [39]Melittin
(Apis m.)
Ulcerative colitisAnimal: mice
Feeding
Anti-oxidant activity
Melittin synthesis via fungi
(Ghorbani et al., 2022) [40]Melittin (bee)Cerebellar ataxiaAnimal: rats
Injection
Anti-apoptotic
Neurological
(Zan et al., 2024) [41]Melittin (bee)Sepsis-induced acute kidney injuryAnimal: mice
Injection, Hk-2 cell line
Gene Expression-Pathway
Anti-cell death Ferroptosis
(T. Wang et al., 2016) [42]Melittin (honeybee)MyocarditisAnimal: mice
Injection
Pathway interactions
(Leem, et al., 2021) [43]Melittin (bee)Acute kidney injuryAnimal: mice
Injection
Anti-apoptotic
Anti-oxidant activity
(Fan et al., 2021) [44]Melittin (bee)Acute liver failureAnimal: mice
Injection
Pathway interactions
(Aghighi et al., 2022) [45]Melittin (honeybee)Cerebellar ataxiaAnimal: rats
Injection
Anti-cell death
Autophagy
Neurological
(Vu et al., 2021) [46]Melittin
(Apis m.)
Intracranial arterial dolichoectasiaAnimal: miceImmunomodulation
Hemolytic activity
Delivery of melittin with nanoparticles: iron oxide
(X. Yao et al., 2024) [47]Melittin (honeybee)Ischemic strokeAnimal: rats
Injection
Apoptosis
Gene Expression -Pathway
Neurological
(H. Kim et al., 2022) [48]Melittin (bee)Lumbar spinal stenosisAnimal: rats
Injection
Gene Expression-Pathway
Immunomodulation
(Z. Liu et al., 2023) [49]Melittin (bee)Allergic contact dermatitisAnimal: mice
Injection
Allergy
Pathway interactions
Delivery of Melittin with nanoparticles
(Xing et al., 2024) [50]Melittin
(Apis m.)
Cerebral ischemiaAnimal: mice
Injection
BV2 cell line
Gene Expression-Pathway
Neuroprotection
(Nguyen, Yoo, An et al., 2022) [51]BV (honeybee)Scopolamine-induced neurodegenerationAnimal: mice
Injection
Anti-oxidant activity
Neuroprotection
Pathway interactions
Delivery of BV: microneedle
(Lee et al., 2020) [52]BV (Apis m.)Acute kidney injuryAnimal: mice
Injection
Anti-oxidant activity
Anti-apoptotic
(J.-Y. Kim, Jang et al., 2021) [53]PLA2 (bee)Cholestatic liver diseaseAnimal: mice
Injection
(D. Shin et al., 2016) [54]PLA2 (bee)Acute lung inflammation
Side Effects of Radiotherapy
Animal: mice
Injection
Immunomodulation
(Keil et al., 2020) [55]Melittin (bee)AsthmaA549, Jurkat T cell lines
GATA3 gene inactivation via siRNA
Immunomodulation
(Mirzavi et al., 2024) [56]BV (honeybee)Colon cancerAnimal: mice
Injection
C26 cell line
Xenograft
Gene Expression-Pathway
Anti-tumor
Anti-oxidant activity
(Erkoc et al., 2022) [57]BV (Apis m.)
Melittin-derived
Breast cancerHEK293T, MDA-MB-231 and RAW264.7 cell linesAnti-tumor
Pathway interactions
(H.-J. An et al., 2016) [58]Melittin (Apis m.)Renal fibrosisAnimal: mice
Injection
NRK-49F cell line
Anti-fibrotic
Gene Expression-Pathway
Kidney
(W.-R. Lee et al., 2014) [59] Melittin (Apis m.)Acne vulgarisAnimal: mice
Injection
HaCat cell line
Gene Expression-Pathway
Skin disease
Protective effects
(Bae et al., 2022) [60]BV (bee)
Melittin
Skin infectionAnimal: mice
Topical administration
Skin disease
(H. An et al., 2018) [61]BV (Apis m.)
Melittin
Atopic dermatitisAnimal: mice
Topical administration
HaCat cell line
Gene Expression-Pathway
Skin disease
(M. Choi et al., 2023) [62]Melittin (honeybee)Alzheimer’s diseaseAnimal: mice
Injection
C166, RAW264.7 cell lines
Neurological
Conjugate with iron oxide
Hemolytic activity
(Z. Wang et al., 2025) [63]MelittinColitis-Associated Mental DisordersAnimal: mice
Delivery
Anti-depressant
(J. Yao, Chen et al., 2025) [64]Melittin
(Honeybee)
OsteoarthritisAnimal,
Delivery
Hydrogel
(Nam et al., 2025) [65]ApaminCerebellar ataxiaDockingGene Expression-Pathway
Neurological
(Romanenko et al., 2025) [66]BVApical periodontitisAnimal: rats
Injection
Anti-inflammatory
(Ayoub et al., 2025) [67]Apis m.HyperalgesiaAnimal: miceGene Expression-Pathway
Neurological, Pain
(J.-W. Yu & Lu, 2025) [68]MelittinPulmonary fibrosisAnimal: miceGene Expression-Pathway
Anti-fibrotic
(T. Yu et al., 2025) [69]MelittinParkinson’s diseaseHT22 cell lineGene Expression-Pathway
Neurological, Anti apoptotic
(Izbicka & Streeper, 2025) [70]PLA2Chronic disease Hemolytic activity
Anti-nociception
(M. Chen et al., 2024) [71] ParkinsonAnimal: mice
SH-SY5Y cell line
Apoptosis
Neurodegeneration
(Cho et al., 2025) [72]BVSLE nephritisAnimal: mice
injection
Gene Expression-Pathway
Skin diseases
Immunomodulation
(Zeng et al., 2025) [73]MelittinPsoriasis vulgarisAnimal: mice
HaCat, HUVEC, RAW264.7 cell lines
Topical administration
Skin diseases
(Niu et al., 2024) [74]MelittinPeriprosthetic osteolysisAnimal: ratsGene Expression-Pathway
Table 4. Anti-inflammatory therapeutic research targeting rheumatoid arthritis.
Table 4. Anti-inflammatory therapeutic research targeting rheumatoid arthritis.
Article NameSubstanceExperimental DesignAdditional Information
(Yousefpoor et al., 2022) [76]BV (Apis mellifera)Animal: rats
Topical administration
Delivery of BV with nanoparticles: nanoemulsion
(G.-M. Choi et al., 2021) [77]PLA2 (honeybee)Animal: mice
Injection
Gene Expression-Pathway
Immunomodulation
(L. Yang et al., 2023) [75]Melittin (bee)In silico analysisDocking, Pharmacology
(S. E. Sharaf et al., 2022) [78]BV (bee)Acupuncture
Clinical Survey
Other bee products
(F. Liu et al., 2023) [79]Melittin (Apis m.)Animal: mice
Injection
Gene Expression-Pathway
(Choe & Kim, 2017) [80]Melittin (Apis m.)Animal: mice
RAW264.7 cell line
Gene Expression-Pathway
Immunomodulation
(Du et al., 2021) [81]Melittin (bee)Animal: mice, rats
Injection
Delivery of melittin with hyaluronic acid via microneedle
(L. Jin et al., 2025) [82]Melittin (bee)Animal: rats
Injection
Microneedle delivery of melittin
(Xiong et al., 2025) [83]Melittin (bee)Animal: rat, pig
Acupuncture
Delivery of melittin by liposome microneedle
Table 5. Anti-inflammatory bioactivity of BV and melittin without a specific disease target.
Table 5. Anti-inflammatory bioactivity of BV and melittin without a specific disease target.
ArticleSubstanceExperimental DesignAdditional Information
(Praphawilai et al., 2024) [84]BV (Apis m.)Vero and RAW264.7 cell lines
HSV-1, HSV-2 Virus, Nitric Oxide Reduction Assay
Anti-viral, Cytotoxicity
Gene expression-Pathway
(W.-H. Kim et al., 2018) [85]Melittin (Apis m.)HaCaT cell line
Bacteria: Porphyromonas sp.
Gene Expression-Pathway, Cytotoxicity
(Im et al., 2016) [86]BV (honeybee)BV2 cell lineCytotoxicity
Pathway interactions
Neurological
(Malan et al., 2016) [87]MelittinRAW264.7 cell lineAnti-endotoxin
Melittin is the only reference
Polimiksin B
(Sevin et al., 2023) [88]Not just melittin, also Apamin, Melittin, PLA2U87MG and RAW264.7 cell lines Immunomodulation
(Abu-Zeid et al., 2021) [89]BV (Apis m.)Animal: rats
Injection
Anti-oxidant activity
Neuroprotective effects
(H.-S. Lee et al., 2021) [90]BVMCF-10A and RAW264.7 cell linesAllergy
(Streeper & Izbicka, 2022) [91] PLA2 (Apis cerana)Human erythrocytesVenom immunotherapy
(Abbasi et al., 2023) [92]BV (honeybee)
Animal: mice
Injection
Gene Expression-Pathway
(Alqarni et al., 2018) [93]Melittin (honeybee)THP-1 cell lineVaccine
(Eid et al., 2022) [94]Melittin (Apis m.)Animal: rats Pathway interactions
Synergy with Diclofenac
(Senturk et al., 2022) [95] BV (Apis m.)Animal: rats
Injection
Anti-oxidant effects
Liver, Skeletal Muscle
Oxidative stress
(Jo et al., 2021) [96]PLA2 (bee)Peripheral blood mononuclear cellsImmunomodulation
(Tseng et al., 2025) [97]Melittin RAW264.7 cell line
Bacteria: Bacillus subtilis
GAL1–MELT fusion protein synthesis via E. coli
Anti-inflammatory activity of recombinant melittin
(Rășinar et al., 2025) [98] BV (Apis m.)2,2-Diphenyl-1-Picrylhydrazyl AssayChemical synthesis of melittin
Anti-oxidant activity
(Q. Zhang et al., 2025) [99] Melittin Schwann cell linesGene Expression-Pathway
Neurological
(H. Zhao et al., 2025) [100]BV, melittinAnimal: miceSkincare, aging
(Lomeli-Lepe et al., 2025) [101] BVAcupoint injection
Animal: mice
Anti-oxidant activity
Neuroprotection
Table 6. Immunomodulatory activity research articles (without cancer).
Table 6. Immunomodulatory activity research articles (without cancer).
ArticleSubstanceDiseaseExperimental DesignAdditional Information
(Basuini, 2024) [102]BV (Apis m.) Animal: Liza ramada
Feeding
Anti-oxidant activity
Characterization of BV
(G.-M. Choi et al., 2021) [77] PLA2 (honeybee)Rheumatoid arthritisAnimal: mice
Injection
Anti-inflammatory
Gene Expression-Pathway
(G.-H. Kang et al., 2020) [29] PLA2 (bee)AtherosclerosisAnimal: mice
Injection
Anti-inflammatory
Gene Expression-Pathway
(Baek et al., 2020) [30]PLA2 (Apis m.)Alzheimer’sAnimal: mice
Primary cell culture
Anti-inflammatory
Apoptosis
Neurological
(Alqarni et al., 2018) [93] Melittin (honeybee) THP-1 cell line
Vaccine
Anti-inflammatory
Gene Expression-Pathway Delivery of melittin
(Karimi et al., 2023) [103] Melittin (honeybee) Animal: mice
Injection
(H. Kim et al., 2022) [48] Melittin (bee)Lumbar spinal stenosisAnimal: rats
Injection
Anti-inflammatory
Gene Expression-Pathway
(Vu et al., 2021) [46] Melittin (Apis m.)Intracranial Arterial DolichoectasiaAnimal: mice
Injection
Anti-inflammatory
Hemolytic activity
Delivery of melittin with nanoparticles: iron oxide
(Z. Liu et al., 2023) [49]Melittin (bee)Allergic contact dermatitisAnimal: mice
Injection
Anti-inflammatory
Gene Expression-Pathway Delivery with nanoparticles
(D. Shin et al., 2016) [54] PLA2 (bee)Acute lung inflammationAnimal: mice
Injection
Anti-inflammatory
Gene Expression-Pathway
Side effects of chemotherapy
(Jo et al., 2021) [96]PLA2 (bee) PBMC cell line Anti-inflammatory
(H. An et al., 2018) [61] BV, Melittin (Apis m.)Atopic dermatitisHaCat cell lineAnti-inflammatory
Gene Expression-Pathway
Skin diseases
(Eweis et al., 2022) [104] BV FMDV (foot-and mouth disease virus)Veterinary
Immunogenicity
(Cho et al., 2025) [72] BV SLE nephritis Skin lesionsAnimal: mice
injection
Gene Expression-Pathway
(S. Kim, Kim et al., 2021) [105]BVAsthmaA549 cell line Allergy
Gene Expression-Pathway
(Seo et al., 2025) [106]MelittinRespiratory diseaseAnimal: mice LNP-MEL
Conjugate with mRNA
(Sylvestre et al., 2021) [107]Melittin Animal: mice Delivery
Conjugate with PEG
L and D-melittin
Immunogenicity
Table 7. Immunomodulatory activity exerted by BV and MEL in cancer research.
Table 7. Immunomodulatory activity exerted by BV and MEL in cancer research.
Article SubstanceCell LinesExperimental DesignAdditional Information
(Bahreyni et al., 2023) [110]Melittin4T1, B16F10, HeLa, MDA-MB-231Synergy
Delivery
Anti-tumor
Melittin derived
(H. Wang et al., 2025) [111] Melittin4T1Animal: mice
Xenograft
Anti-tumor
Melittin synthesis
Conjugate with Promelittin
(Song et al., 2023) [112] Melittin HeLa, B16F10-OVA, DC2.4-Gal8-GFPAnimal: mice
Vaccine
Drug delivery
Cell viability
Immunogenicity
D-melittin
(Sevin et al., 2023) [88] BV (Apis m.), Apamin, Melittin, PLA2U87MG Cytotoxicity
Gene expression-pathway
(Abass et al., 2025) [37] BV (Apis m.) EACAnimal: mice
Xenograft
Anti-inflammatory
Liver
(Shir et al., 2011) [113]Melittin A431, MDA-MB-231, U138MG, U87MGAnimal: mice
Delivery
Gene Expression-Pathway Hemolytic activity
(X. Yu et al., 2019) [114] Melittin 4T1, B16F10, CT26 Animal: mice
Delivery
Anti-metastatic
Gene Expression-Pathway
(P. Wu et al., 2022) [115] Melittin 4T1, HEP1-6 Animal: mice
Synergy
siRNA
Delivery
Anti-metastatic
melittin synthesis
Apoptosis
Gene expression-pathway
(C. Lee et al., 2017) [116] Melittin LCC, MLE12, H441 Animal: mice Anti-tumor, ROS (reactive oxidative species)
Gene expression-pathway
(M. Liu et al., 2016) [117] Melittin A549, CTLL-2, SMMC-7721, MDA-MB-231, SKOV3Animal: mice
Melittin fusion design
Anti-metastatic
Cytotoxicity
(Guo et al., 2023) [118] Melittin 4T1Animal: mice
Delivery
Anti-tumor
Hemolytic activity
(Tang et al., 2022) [119] MelittinB16F10, B16, MB-49, MC38, MC38-OVAAnimal: mice
Delivery with MnO2
Vaccine
Anti-tumor
Cytotoxicity
(K. Yang et al., 2023) [120]
MelittinB16-luc, B16F10Animal: mice
Vaccine
Delivery with hydrogel
Anti-tumor
Cytotoxicity
Hemolytic activity
(Keil et al., 2020) [55] Melittin A549, Jurkat T Delivery Anti-inflammatory
Melittin is only reference
Endosomal escape with melittin
Asthma
(I.-H. Han et al., 2022) [121]Melittin B16F10, THP-1 Animal: mice Anti-tumor
Gene expression-pathway
(Hamze Mostafavi et al., 2025) [122]MelittinBT-474, NIH3T3Delivery
Synergy with Trastuzumab
Melittin synthesis via Bacteria: E. coli
(Shen et al., 2024) [123] MelittinCT26, NIH3T3, HUVEC, CAF Animal: mice
Delivery
Synergy
Hemolytic activity
(Gasanoff et al., 2021) [124]MelittinJurkat TDocking Cytotoxicity
Membrane interactions
(Dai et al., 2025) [125] Melittin Breast Cancer Animal: mice
Delivery
Gene Expression-Pathway
(D. Zhang et al., 2025) [126]Melittin 4T1Animal: mice
Delivery
Injection
Anti-oxidant activity
With HA and Fe
ROS
Table 8. Research articles describing the anti-bacterial (ABA), anti-fungal (AFA), and anti-viral (AVA) activity of bee venom and melittin.
Table 8. Research articles describing the anti-bacterial (ABA), anti-fungal (AFA), and anti-viral (AVA) activity of bee venom and melittin.
ArticleExerted BioactivitySubstanceExperimental DesignAdditional Information
(W. Zhu et al., 2021) [128]AMP, ABAMelittinE. coliMelittin synthesis via E. coli
(Akbari et al., 2018) [129]AMP, ABAMelittin-derived peptides (MDP1, MDP2)S. aureus, E. coli, and P. aeruginosaMembrane damage
(Ludwig et al., 2025) [131]AMP, ABANot just Melittin, but also cathelicidin-related AMP (CRAMP) Melittin synthesis via E. coli
Cathelicidin-related
delivery
Gene Expression-Pathway
(W.-H. Kim et al., 2018) [85]ABA, cytotoxicityBV (Apis m.), MelittinPorphyromonas gingivalisAnti-inflammatory
Gene Expression-Pathway
(Enigk et al., 2020) [132] AMP, ABA, AFA, hemolytic activity Not just Melittin, but also nisin, lactoferrin, parasin-1 and LL-37C. albicans, P. aeruginosa, S. aureus
(Tanuğur-Samancı & Kekeçoğlu, 2021) [133]ABA, AFABV (Apis m.)S. aureus, C. albicans, E. coliAnatolian BV content Melittin 40.57%
(J. Yang et al., 2017) [134]ABA, Enzymatic, Hemolytic, Anti-fibrinolytic activityA. cerana venom serine protease inhibitor (AcVSPI) Beauveria bassiana, Bacillus thuringiensis, E. coliAnti-microbial roles of AcVSPI
(Pérez-Delgado et al., 2023) [135]ABA, Hemolytic and Anti-oxidant activityBV (Apis m.)E. coli, P. aeruginosa, S. aureus
(Arteaga et al., 2019) [136]ABA, Anti-biofilmApitoxin of Apis m.16 Salmonella strains
(Socarras et al., 2017) [137]Anti-biofilm activity, ABA,BV (Apis m.) and MelittinAntibiotic-resistant Borrelia burgdorferi Antibiotic resistance
(Y. Liu et al., 2023) [138]AMP, ABA,Melittin-derived peptide; Melittin-Thanatin fusion (MT-W)Antibiotic resistant E. coli, Streptococcus pyogenes, and othersComparison of melittin to MT-W
(Gourkhede et al., 2020) [139]ABA, AMP, Hemolytic activity, Cytotoxicity Melittin-derived peptide; Cecropin A (1–7)-Melittin (CAMA) and lactoferricinAntibiotic resistant Salmonella Enteritidis strains, E. coliMulti-drug resistance
(Shi et al., 2016) [140]AMP, ABAMelittinXanthomonas oryzaePlant protection,
Molecular effect of melittin on cell membranes, energy metabolism and nucleic acid & protein synthesis
(Huan et al., 2022) [141]AMP, Hemolytic activity, cytotoxicity, ABAMelittin derived; Mel-d1, and LVFF-CONH2E. coli, Listeria monocytogenes, Vibrio ParahemolyticusComparison with melittin
(K. Bakhiet et al., 2022) [142]ABA, AFABV (Apis m.)E. coli, S. aureus, Serratia marcescens,
(X. Su et al., 2023) [130]ABA, cytotoxicityMelittinE. coli, S. aureusDelivery of melittin, Therapeutic
(S. Han et al., 2016) [143]ABABV (Apis m.)Methicillin-Resistant S. aureus (MRSA) Antibiotic resistance
(Dosler et al., 2016) [144]AMP, ABA, anti-biofilm activityBV (Apis m.), not just melittinE. coli, K. (Klebsiella) pneumoniae, P. aeruginosaAntibiotic resistance
(F. Yang et al., 2023) [145]AMP, ABA, hemolytic activityNot just melittin, cationic AMPS. aureus, E. coliSkin care
(Chudinova et al., 2016) [146]AMP, ABANot just melittin,
Warnerin
E. coli, Staphylococcus epidermidisDelivery of melittin
(Lima et al., 2022) [147]ABA, anti-biofilm, anti-adhesive activityMelittin from BVQuinolone-resistant uropathogenic E. coli (UPEC)BV content analysis
(Mirzaei et al., 2023) [148]ABA, cytotoxicity, and anti-biofilm activity Melittin MRSA
P. aeruginosa
Synergy with antibiotics
Gene Expression-Pathway
Melittin synthesis
(Kuzmenkov et al., 2022) [149]ABAApamin from BV (Apis m.) MRSA, E. coli, Enterococcus faecalis Pharmaceutical
Simulation
(W. A. Sarhan & Azzazy, 2017) [150]ABA, cytotoxicityNot just BV, also flavonal Nano delivery of bee venom
(Strömstedt et al., 2017) [151]ABA, AFANot just BV (Apis m.), CyclotidesE. coli, S. aureus, P. aeruginosa, C. albicansBV derived peptides
(Zolfagharian et al., 2016) [152]ABABV (Apis m.)E. coli, S. aureus, P. aeruginosa, Antibiotic resistance
(Gökmen et al., 2023) [153]ABABV (Apis m.)E. coli, K. pneumoniae,
S. aureus
drug resistance, BV content analysis,
MDR
(Moridi et al., 2020) [154]AMP, ABAMelittinMRSA, S. aureus, Serratia marcescens Melittin synthesis via E. coli
(Jiang et al., 2019) [155]AMP, ABA, hemolytic activity, cytotoxicity,Melittin-derived peptides; thanatinE. coli,
Bacillus subtilis,
Salmonella Typhimurium
Synergy with melittin
(Lu et al., 2019) [156]AMP, ABAMelittin-derived peptide; Melittin-Graphene hybridE. coli,
S. aureus
Nano Delivery
Membrane interactions
(Akhzari et al., 2021) [157]Anti-parasitic activity, Anti-inflammatory, cytotoxicityMelittinLeishmania sp.Synergy,
Gene Expression-Pathway
(Kabakci et al., 2023) [158]ABABV (Apis m.)Aeromonas hydrophila,
Lactococcus garvieae,
Vibrio anguillarum,
Yersinia ruckeri
Gene Expression-Pathway, antibiotic resistance
(Sahsuvar et al., 2023) [159]AMP, ABA, cytotoxicity, ROS, hemolytic, Anti-oxidant activityMelittin-derived peptide; Melittin-folic acid E. coliSynergy
(Vaiwala et al., 2022) [160]AMP, ABAMelittin-derived; melittin-peptidoglycanMRSA, E. coli,
S. aureus
Membrane interactions
(H. Yang et al., 2024) [161]AMP, ABA, ROS, anti-biofilm activityMelittin E. coli, K. pneumoniae
S. aureus,
Anti-quorum sensing
(Jamasbi et al., 2018) [162]ABA, ROS,
Cytotoxicity, hemolytic activity
MelittinE. coli, K. pneumoniae,
Acinetobacter baumannii
Chemical synthesis of melittin
(Z. Li et al., 2023) [163]ABA, Anti-oxidant activityMelittin Gut bacteria
(Ravensdale et al., 2016) [164]AMP, ABA, hemolytic activityNot just melittin, mel12-26, bac8c peptidesMRSA S. aureusDrug resistance
(Jeon et al., 2024) [165]AMP, ABA, hemolytic, Anti-inflammatory
Cytotoxicity
Anti-biofilm activity
Not just melittin, Osmin K. pneumoniaeDrug resistance
(Ji et al., 2017) [166]AMP, ABAMelittin derived; cecropin-A-melittin
(CAM-W)
Bacillus subtilis, E. coli,
Streptococcus pyogenes
Heterologous melittin synthesis in Bacillus subtilis
(F. Wang et al., 2023) [167]AMP, ABAMelittin-derived; melittin-EAP fibrilsBacillus subtilis,
E. coli, Streptococcus pyogenes, and others
Peptide synthesis
Melittin fusion design
(Bevalian et al., 2021) [168]AMP, ABA, cytotoxicityMelittinVancomycin Resistance S. aureusAntibiotic resistance
Wound dressing
(X. Kang et al., 2024) [169]AMP, ABA, cytotoxicityNot just melittin, also
Pexiganan, plectasin, and cathelicidin
E. coli, K. pneumonia
S. aureus
Bacterial vaginosis disease
(El-Sayied Ali et al., 2024) [170]ABABV Paenibacillus larvaeNano delivery of BV
(Vergis et al., 2021) [171]AMP, ABA, cytotoxicity, hemolytic activityCecropin-A-melittin E. coli, Lactobacillus acidophilus,
Lactobacillus rhamnosus
Antibiotic resistance,
Laboratory model Galleria mellonella
(L. Zhou et al., 2020) [172]ABAMelittin E. coli, Staphylococcus pasteuri, MET-GST (Melittin and glutathione-S-transferase fusion)Melittin synthesis via E. coli
(Abou Zekry et al., 2020) [173]ABA, cytotoxicity Not just BV, also other bee productsE. coli, S. aureusNano delivery of BV
Synergy
(Frangieh et al., 2019) [174]ABA, hemolytic, cytotoxicity, and Anti-oxidant activityBV (Apis m. syriaca)E. coli, S. aureus, B. subtilisBV content analysis
(S. Xiao et al., 2019) [175]AMP, ABAMelittinE. coli,
S. aureus
Nano delivery
Membrane interactions
(Bardbari et al., 2018) [176]AMP, ABA, anti-biofilm activityNot just melittin; melittin with imipenem and colistinA. baumanniiSynergy,
Gene Expression-Pathway
(Mirzaei et al., 2022) [177]ABAMelittinS. epidermidisSynergy with antibiotics
(Gong et al., 2023) [178]AMP, ABA, hemolytic activityNot just melittin E. coliMembrane interactions of melittin
(Stephani et al., 2024) [179]AMP, ABAMelittin Gram-negative bacteria Docking
Membrane interactions
(Maiden et al., 2019) [180]AMP ABA, Anti-inflammatory,
Anti-biofilm activity
Not just melittin, Tobramycin P. aeruginosaNano delivery
Synergy
(Zarghami et al., 2022) [181]AMP ABA, cytotoxicityMelittinMRSA Nano delivery
(Birteksoz-Tan et al., 2019) [182]AMP, ABA, Anti-biofilm activityMelittin derived;
Cecropin-A-melittin
S. aureus,
Legionella pneumophila
(Marques Pereira et al., 2020) [183]AMP, ABANot just Melittin also BV (apitoxin)MRSA
(Liao et al., 2023) [184]AMP, ABANot just Melittin, also G(IIKK)3I-NH2 (G3) and G(IIKK)4I-NH2 (G4) peptidesE. coli
(Rouhi et al., 2024) [185]ABA, Anti-biofilm activityMelittin Listeria monocytogenesGene Expression-Pathway
(Shams Khozani et al., 2019) [186]AMP, ABA, Anti-biofilm activityMelittinP. aeruginosaMelittin synthesis, MDR
(El-Didamony et al., 2024) [187]AMP, ABA, cytotoxicity, Anti-biofilm activityMelittin derived; melittin alcalase-hydrolusateE. coli, Bacillus cereus,
Enterococcus faecalis
BV content analysis
(Zarghami et al., 2021) [188]AMP, ABA, cytotoxicity, Anti-biofilm activityMelittin-derived; chitosan-antibiotic coating melittinMRSA
VRSA
Nano delivery by chitosan
Synergy with
antibiotic
(Galdiero et al., 2019) [189]AMP, ABA, Anti-biofilm activityMelittin K. pneumoniae, P. aeruginosa, Aeromonas caviaeDrug resistance
(Alajmi et al., 2022) [190]AMP, ABABV (Apis m. yemenitica, Apis m. carnica)E. coli, S. aureus, P. aeruginosa, Salmonella TyphimuriumAntibiotic resistance
(Mandal & Mandal, 2024) [191]AMP, ABANot just melittin; MM-GBSA and QM/MMAcinetobacter baumanniiIn silico analysis
(Saraswat, Wani et al., 2020) [192]AMP, ABA, hemolytic activity, cytotoxicityMelittin-derived; with ionic liquidsE. coli, S. aureusConjugate
(Chetty et al., 2022) [193]ABA, hemolytic activityMelittin-derived; cecropin-A-melittin analogs, CA(1–7)M(2–9)E. coli, P. aeruginosa,
S. aureus, Bacillus subtilis
(L. Yu et al., 2021) [194]ABANot just Melittin, also alpha helical peptideMRSA, Acinetobacter baumanniiComparison with melittin
(Rangel et al., 2020) [195]ABA, anti-biofilmMelittin Acinetobacter baumanniiMembrane interactions
(AL-Ani et al., 2015) [196]ABA, AFABV, melittinE. coli, Klebsiella sp., Staphylococcus sp., C. albicansSynergy with antibiotics
Drug resistance
(Babaeekhou et al., 2023) [197]ABA, anti-biofilm activityMelittin Acinetobacter baumanniiSynergy
Gene Expression-Pathway
(Nehme et al., 2020) [198]ABAMelittin and PLA2 from BV (Apis m.)E. coli,Antibiotic resistance
(Zarghami, Ghorbani, Bagheri et al., 2021) [199]ABA, Anti-inflammatory, anti-biofilm activityMelittinMRSA
VRSA
Nano delivery by chitosan/bioactive glass/vancomycin coatings
(S.-K. Zhang et al., 2016) [200]AMP, ABA,Melittin derived; Ar-23 and rv-23E. coli, S. aureusMembrane interactions of melittin
(Pashaei et al., 2019) [201]ABAMelittinDrug-resistant
Acinetobacter spp.
Toxicity
(Brand & Khairalla, 2021) [202]ABAMelittinGram-negative bacteriaMembrane interactions
(Hakimi Alni et al., 2020) [203]ABA, cytotoxicity
Anti-biofilm activity
Not just melittin, also
Mupirocin
MRSA
MSSA
Synergy with melittin,
Gene Expression-Pathway
(Pereira et al., 2023) [204]ABANot just melittin, but also OxacillinMRSA Synergy with melittin
(Mahmoudi et al., 2020) [205]ABA, hemolytic activity,Not just melittin, but also clindamycinMRSA
MSSA
Synergy with melittin,
Gene Expression-Pathway
(Güven Gökmen et al., 2023) [206]ABA, Anti-inflammatoryBV (Apis m.)Serratia marcescens,
Acinetobacter lwoffii,
Pseudomonas sp.
Veterinary
Antibiotic resistance,
Subclinical mastitis (Cow disease)
(W.-R. Lee et al., 2014) [59]ABA, Anti-inflammatory, cytotoxicityMelittin Propionibacterium acnesGene Expression-Pathway
(Rad et al., 2024) [207]AMP, ABA, cytotoxicity,
Hemolytic activity
Melittin-derived peptides; M1 and M2
Staphylococcus sp.,
Enterococcus faecalis,
E. coli
(Bae et al., 2022) [60]ABA, Anti-inflammatoryMelittin and BV (Apis m.)Streptococcus pyogenesAnimal
Skin diseases
(Oehler et al., 2023) [208]AMP, ABAMelittin derived; EncapsulatedE. faecium,
S. aureus, A. baumannii
Microemulsion (BMEs)
(M. Sharaf et al., 2024) [209]Cytotoxicity, ABA, AFAApitoxin of BV (Apis m.) encapsulated in chitosan nanoparticlesS. aureus, Staphylococcus hominis, E. coliNanotreatment
(Ahmed et al., 2024) [210]ABA, AFABV (Apis m.)E. coli, S. aureus,
B. cereus
Natural preservative
(M. Sharaf et al., 2023) [211]Anti-biofilm activity, ABABV (Apis m.), Nanoflowers loaded BV (Bv-ZnO@αFe2O3)54 fecal Antibiotic-resistant strains (E. coli, Klebsiella strains)
(Ji et al., 2014) [212]AMP, ABA, AFAMelittin derived; Cecropin A–melittin mutants (CAM-W)E. coli, Campylobacter jejuni, Helicobacter pylori
(Gülmez et al., 2017) [213]Cytotoxicity, ABABV (Apis m.)Multi Drug Resistant (MDR) strains; E. faecium, E. coliGene expression pathway
(A. Kamel et al., 2021) [214]Cytotoxicity, ABABV (Apis m.)Multi Drug Resistant (MDR) 62 clinical bacteria isolates (P. aeruginosa strains)Synergistic effect with antibacterial drugs
(Abdel-Monsef et al., 2023) [215]Cytotoxicity, ABA, AFASuperoxide dismutase (SOD) of BV (Apis m.)Proteus mirabilis,
Salmonella typhi,
C. albicans
(Sonmez et al., 2022) [10]AMP, ABABV (Apis m.)S. aureus, B. cereus,
S. enterica
(Sullivan et al., 2011) [216]AMP, Anti-biofilm, ABANot just Melittin B, also C16G2, AMP G2Streptococcus mutansMouth wash
(Maitip et al., 2021) [217]AMP, ABA, AFABV (Apis m., A. Cerana, A. Dorsata and A. Florea), melittinStaphylococcus sp., MRSA,
Bacillus subtilis
(Tanuğur Samancı & Kekeçoğlu, 2022) [218]Cytotoxicity, Anti-oxidant, anti-aging, ABA, AFABV, also bee products; honey, propolis, beeswax, and royal jelly.P. aeruginosa, S. aureus,
E. coli, C. albicans
Prototype body cream
(Radhakrishnan et al., 2024) [219]AMP, Cytotoxicity, Hemolytic activity, anti-biofilm, ABAMelittin-derived Mel-LX3MDR P. aeruginosa,
MRSA, Staphylococcus sp.
(Celebi et al., 2023) [220]Anti-biofilm, Cytotoxicity, ABABVE. coliSynergy of BV
Combination with Amoxicillin-clavulanic acid
(Akbari et al., 2022) [221]AMP, Cytotoxicity, Hemolytic activity, ABAMelittin-derived peptides; MDP1,2MDR strains of S. aureus, E. coli, and P. aeruginosaDe novo designed Melittin-derived peptides
(Harries et al., 2013) [222]AMP, AFANot just Melittin, also PAF26, P113 and cecropin A peptidesSaccharomyces cerevisiae strainsGene Expression-Pathway
Membrane interactions
(Q. Chen et al., 2021) [223]AMP, Hemolytic activity, Cytotoxicity, ABAMelittinE. coli, Shigella flexneri, S. aureusMelittin synthesis via E. coli
(Ferreira et al., 2021) [224]AMP, ABAMelittin derived; Cecropin A-melittin hybrid peptide BP100, W-BP100P. aeruginosa, E. coli,
S. aureus, Enterococcus faecalis
(Thankappan et al., 2023) [225]AMP, Hemolytic activity, Cytotoxicity, ABAMelittin and melnpP. aeruginosa, E. coli,
S. aureus
Melittin nanoparticles
(Askari et al., 2021) [226]AMP, Hemolytic activity, Cytotoxicity, ABAMelittin Drug-resistant (XDR) Acinetobacter baumannii, MRSA, and K. pneumoniaeMelittin synthesis via fungi
(Elswaby et al., 2022) [227]Anti-oxidant activity, ABA, AFABV and also propolisS. Typhimurium,
E. coli, B. cereus
(Picoli et al., 2017) [228]AMP, Anti-biofilm activity, ABAMelittinS. aureus, E. coli
P. aeruginosa
(Aburayan et al., 2022) [229]AMP, Cytotoxicity, ABA, AFAMelittinMRSA, P. aeruginosa,
E. coli
Delivery coated by Polyvinylpyrrolidone
(Alvarez et al., 2022) [230]AMP, ABAMelittinGram-negative and Gram-positive bacteriaNano fiber design
(Hejníková et al., 2024) [231]AMP, ABABV (Apis m.) and melittinE. coli, L. monocytogenesGene expression analysis
(Choo et al., 2010) AMP, ABAMelittin, bombolitinGram-positive and two Gram-negative bacteria
(Bui Thi Phuong et al., 2024) []AMP, Hemolytic activity, Cytotoxicity, ABA, AFAMelittin-derived peptides; BP52- based on Melittin M and Cecropin AB.s cereus,
E. faecalis,
L.monocytogenes
(S. Huang et al., 2024) [232]AMP, Hemolytic activity, ABAMelittin derived; Mel-C8S. aureus, E. faecalis, E. coliMembrane permeabilization
(Babaie et al., 2020) [233]ABANot just BV (Apis m.). Also snake scorpionS. aureus, B. subtilis, P. aeruginosa, E. coli
(Pola et al., 2023) [234]AMP, ABA, AFAOther halictine peptides of BVA. baumannii,
E. coli, S. epidermidis, S. aureus
Delivery by polymer-PEP
(Nabizadeh et al., 2023) [235]AMP, ABAMelittin and Lasioglossin hybrid peptidesA. baumannii and S. aureusSimulation study
(Chou et al., 2021) [236]AMP, Anti-biofilm activity, Cytotoxicity, ABA, AFANot just melittin, also P19 peptide.E. coli, S. aureusMembrane permeabilization
(Saraswat, Aldahmash et al., 2020) [192]AMP, Cytotoxicity, ABANot just Melittin, also combination with ionic liquids (ils) E. coli and S. aureus
(Pourahmadi et al., 2022) [237]AMP, Anti-biofilm activity, ABABMAP27-Melittin conjugate39 Streptococcus mutans strainsClinical Isolates from Oral Cavity
(López-García et al., 2010) [238]AMP, AFANot just melittin Saccharomyces cerevisiaeSynergy
Gene expression-pathway
(Y. Yang et al., 2020) [239]AMP, Hemolytic activity, ROS activity, Cytotoxicity, AFANot just melittin, alfa helical peptide, C. albicansDrug resistance
(Tanuğur-Samanc & Kekeçoğlu, 2021) [133]AFA, ABABV (Apis m.)C. albicans, E. coli
S. aureus
Chemical profiling of Anatolian BV
(Kočendová et al., 2019) [240] AMP, AFA, Hemolytic, Cytotoxicity, anti-biofilmBV-derived peptidesCandida strains
(S.-B. Lee, 2016) [241]AFABV (Apis m.)C. albicans
(El-Didamony, Kalaba et al., 2022) [242]Anti-biofilm, AFABVC. albicans, Cryptococcus neoformans, Kodamaea ohmeriDelivery loaded on chitosan nanoparticles
(J.-Y. Kim, Park et al., 2020) [243]AFA, AMP, ROS activity,Melittin-derived Hn-Mc peptideCandida sp., Fusarium sp.,
Trichosporon sp., Aspergillus flavus
Apoptosis
(J. Park et al., 2018) [244]AFABV (Apis m.) and apaminTrichophyton rubrum
(Todorova et al., 2024) [245]AFA, cytotoxicity, genotoxicityBVSaccharomyces cerevisiaeGene Expression-Pathway,
Oxidative stress
(Hilpert et al., 2023) [246]AMP, AFANot just melittin, Cecropin A-melittin hybridC. albicansBioSAXS measurements
(Do et al., 2014) [247]AMP, AFA, cytotoxicityNot just melittin, Cecropin A, protegrin-1 and histatin 5C. albicans Skin penetration
(Y.-M. Kim et al., 2024) [248]AMP, AFA, ROS activity,Melittin derived, WIK-14, C. albicans, Candida krusei, Candida parapsilosisAnimal
(Mahmoud et al., 2024) [249]AMP, AFABV (Apis m.)Vairimorpha ceranaeGene Expression-Pathway,
Bee disease
(C. Park & Lee, 2010) [250]AMP, AFA, ROS,Melittin and BV (Apis m.)C. albicansApoptosis
(E. J. Lim et al., 2022) [251] AMP, AFANot just melittin, also magainin 2, cecropin A, and mastoparan B peptidesC. albicans,
Candida sp.
Compared with melittin
(D. Yu et al., 2022) [252] AMP, AFA, ROS, cytotoxicity, anti-biofilm activityMelittin-derived peptides; lactoferrin and zinc loadedC. albicansMelittin nano delivery
(S.-H. Shin et al., 2017) [253]AMP, AFA, cytotoxicityBV, Melittin and ApaminAlternaria and Aspergillus sp.Gene Expression-Pathway
(G. N. Kim, Choi et al., 2021) [254]Anti-viral peptide, AVA, cytotoxicityMelittin-derived vaccineSARS-CoV-2Vaccine,
Melittin signal peptide
SARS-CoV-2
(Peskova et al., 2017) [255] Anti-viral peptide, AVA, cytotoxicity, hemolytic activity,Not just melittin, CAM-W, GALA, SMAP29, KALA peptidesLentivirusEbola
(Praphawilai et al., 2024) [84]AVA, cytotoxicityBV (Apis m.)HSV-1, HSV-2Anti-inflammatory
(D.-H. Kim et al., 2020) [256]AVA, cytotoxicityBVHPVApoptosis,
Gene Expression-Pathway, SARS-CoV-2
(Männle et al., 2020) [257]AVABVSARS-CoV-2SARS-CoV-2
(Hood et al., 2013) [258]AVA, cytotoxicity, Melittin deliveryHIV-1Nano delivery
(E. Choi et al., 2016) [259]AVA, cytotoxicityMelittin deliveryHIV-1Vaccine, immunogenicity
(Enayathullah et al., 2022) [260]AVA, cytotoxicityNot just melittin, also Gramicidin SSARS-CoV-2Therapeutic
(Dehghani et al., 2020) [261]AVAMelittinHIVIn Silico Analysis, simulation
(Mustafa et al., 2023) [262]AVABV elementsCapripoxvirusIn Silico Analysis
(Muzammal et al., 2022) [263]AVABV elements; PLA2Ebola VirusIn Silico Analysis
(Baldassi et al., 2022) [264]AVAMelittinSARS-CoV-2Membrane interactions Melittin nano delivery
(Uddin et al., 2016) [265] AVA, cytotoxicityMelittin and BV (Apis m.)Influenza A virus (PR8),
Vesicular Stomatitis Virus,
Respiratory Syncytial Virus, Herpes Simplex Virus
(Chianese et al., 2023) [266]Anti-microbial peptide, AVA, cytotoxicityMelittin-derived peptides; RV-23 and AR-23 Sandfly Fever Naples Virus (SFNV)
(Das Neves et al., 2016) [267]AVANot just melittinHuman immunodeficiency virus (HIV)Melittin nano delivery
(M. Sarhan et al., 2020) [268]AVA, cytotoxicityBV elements (Apamin, melittin, mast cell degranulating (MCD) peptide)Hepatitis C virusGene expression
(Abd El Maksoud et al., 2024) [269]AVA, cytotoxicityNot just BV (Apis m.), also Vespa orientalisSARS-CoV-2In silico and In vitro
(Farhoudi et al., 2022) [270]AVAMelittin (Apis m.), melittin hybrid designSARS-CoV-2In silico analysis, docking
(Al-Rabia et al., 2021) [271]AVAMelittin and Angiotensin SARS-CoV-2In silico analysis, docking
(Elnosary et al., 2023) [272] AVA, ABABVMERS-CoV,
S. aureus, Bacillus subtilis,
P. aeruginosa
Delivery of bee venom loaded chitosan, nanoparticle
(Abd-El-Samie et al., 2024) [8]AVA, Hemolytic activity, cytotoxicityBV (Apis m.)Bee viruses; Black Queen Cell Virus (BQCV), Deformed Wing Virus (DWV), Kakugo, Varroa Destructor Virus-1 (VDV-1)BV content analysis, Hyaluronidase and pla2
(Hartmann et al., 2016) [273]AVAMelittinFeline Immunodeficiency Virus (FIV)Cat study, Veterinary
(Z. Lai et al., 2024) [274] AFA, ABAMelittin E. faecalis, P. aeruginosa, Salmonella pullorumPeptide design
(Hu et al., 2025) [275]ABA, AMPBVE. coli and Salmonella entericaROS, cytotoxicity
Hemolytic activity
(Teiba et al., 2025) [276]ABABVE. colinot just BV
(El-Bilawy et al., 2025) [277]
ABABVE. coli, E. faecalis, S. TyphimuriumChemical profiling of BV
(J. H. Kim et al., 2019) [278]AFABV (Apis m.)Malassezia spp. strainsSkin diseases
(C.-Y. Zhao et al., 2025) [279]ABA MelittinE. coliMelittin resistance
(Sonmez et al., 2025) [280]ABABV (Apis m.)Paenibacillus larvaeChemical profiling
(Lima et al., 2021) [281]ABA, Anti-biofilmMelittinMRSA, S. aureus Wound dressing
(Fahad Alharbi et al., 2025) [282]ABA, AMP, Anti-biofilmMelittin derived, CMEL, CMEL-M1A. baumannii
(Kumar et al., 2025) [283] ABA, AMP, Anti-biofilmMelittin, 19 other AMPs (hirunipins)E. coli, S. aureus, S. epidermidisMelittin as positive control
(Ramos-Alcántara et al., 2025) [284]ABA, AMP, Hydrolytic activityMelittinE. coli, K. pneumoniaeGene Expression-Pathway
(Reyad et al., 2025) [285] ABABV E. coli, K. pneumoniae, P. aeruginosaSynergy
Chemical profiling
Antibiotic resistance
(X. Xu et al., 2025) [286] ABAMelittinMRSA, E. coli, S. aureusMelittin-derived peptide synthesis
(X. Yang et al., 2025) [287] ABA, hemolytic activityMelittin S. pyogenesGlycolization of peptide,
(J. Yao, Li et al., 2025) [288] ABA, AMP, Anti-oxidant activityMelittin Animal: rats
E. coli, S.aereus
ROS, Delivery,
Synergy with Cu2+
(X. Wu et al., 2016) [289] ABA, AMP, CytotoxicityMelittin Docking
Listeria spp.
(Ni et al., 2025) [290] ABA, AMP, Proangiogenic activityMelittin HydrogelDelivery,
Wound dressing
(Maleki et al., 2016) [291] ABA, AMPMelittin cecropin-A conjugateE. coliNanodelivery with iron oxide
(Z. Yang et al., 2025) [292] ABA, Anti- biofilmMelittinS. aureus, P. aeruginosa Candida sp.ROS
Food preservative
(Awad et al., 2025) [293]ABA, Anti- biofilmApis melliferaLactiplantibacillus plantarumGene Expression-Pathway
(W. Chen et al., 2019) [294]ABA, AMP, CytotoxicityMelittin E. coliDelivery,
Membrane interactions
(Tseng et al., 2025) [97]ABA, Anti-inflammatoryMelittinBacillus subtilisGAL1–MELT fusion protein, Melittin synthesis via E. coli
Table 12. Research on the anti-oxidant activity of bee venom and melittin.
Table 12. Research on the anti-oxidant activity of bee venom and melittin.
Article SubstanceDiseaseExperimental DesignAdditional Information
(Z. Li et al., 2025) [19] Melittin Heat stress induced immune organ damage in ducksAnimal: ducksGene expression
Heat-stressed ducks
(Pérez-Delgado et al., 2023) [135]BV (Apis m.) Africanized honeybee Anti-microbial
Hemolytic activity
(Ahmedy et al., 2020) [17]Melittin
(Apis m.)
Acetic acid- induced ulcerative colitisAnimal: miceAnti-inflammatory
Chronic disease
(Rășinar et al., 2025) [98]BV (Apis m.) Chemical profiling of BV
(2,2-diphenyl-1-picrylhydrazyl) DPPH assay
(Nguyen, Yoo, Hwang et al., 2022) [308]BV (Apis m.) Animal: mice injection
Cell line HT22
Cytotoxicity
Gene expression pathway
Neuroprotection
(Abdelrahaman et al., 2025) [22]BV (Apis m.) Gentamicin induced kidney injuryAnimal: rats
Injection
Anti-inflammatory
Gene expression-pathway
Lipid peroxidation
(Aly et al., 2023) [23]BV (Apis m.) EpilepsyAnimal: rats
Injection
Acupuncture
Anti-inflammatory
Neurological
(Abu-Zeid et al., 2021) [89]BV (Apis m.) Animal: rats
Injection
Anti-inflammatory
Neuroprotective
(Badawi et al., 2020) [26]BV
(Apis m.)
Parkinson’sAnimal: mice
Injection synergy with L-dopa
Anti-inflammatory
Neurological
(Basuini, 2024) [102]BV (Apis m.) Animal: Liza ramada (fish) Characterization of BV [35]Immunomodulation
(Sobral et al., 2016) [323] BV (Apis m.) Hela, NCI-H460, Raw264.7,
HePG2, MCF-7 cell lines
Anti-inflammatory
Cytotoxicity
Characterization of BV
(Shaik et al., 2023) [35] Melittin (honeybee) Diabetes Animal: rats
Injection
Synergy with cordycepin
Nanoparticle
Anti-inflammatory
Pro-angiogenetic
Wound dressing/healing
Conjugate
(H.-S. Lee et al., 2021) [90]BV Raw264.7, MCF-10A Cell linesAnti-inflammatory
Allergy
Cytotoxicity
(Sahsuvar et al., 2023) [159]Melittin Cervical cancer Nsf, MCF-7, C33a, HeLa, 3T3 Cell lines
Bacteria: E. coli
Synergy
Conjugate
Anti-bacterial
Cytotoxicity
Folic acid
Melittin hybrid
Hemolytic activity
(Tanuğur Samancı & Kekeçoğlu, 2022) [218]BV Bee products: Honey
Propolis, Royal jelly
Anti-microbial
Anti-aging
Cytotoxicity
Skin care
(Z. Li et al., 2023) [163]Melittin Animal: quail gutAnti-bacterial
(Hegazi et al., 2023) [38]BV Acupuncture
Clinical
Anti-inflammatory
Hemolytic activity
Chronic neck pain
(Yaghoubi et al., 2022) [39] Melittin
(Apis m.)
Ulcerative colitisAnimal: mice
Delivery of melittin
Melittin synthesis via fungi
Anti-inflammatory
Oxidative stress
(Frangieh et al., 2019) [174]BV, PLA2 (Apis m.)Breast cancerMCF-7, 3T3 cell lines
Chemical profiling of BV
Anti-bacterial
Hemolytic activity
(H. G. Park et al., 2018) [428] BV elements (Apis cerana) Apoptosis
Anti-microbial
Cytotoxicity
ROS
(Alhage et al., 2018) [429]PLA2
(Apis m.)
DPPH assayAdverse effects of PLA2
(Elswaby et al., 2022) [227] BV (honeybee) Anti-microbial
Propolis
(Sani et al., 2022) [430]Melittin
(Apis m.)
Membrane interactions
Propolis
(H. Jung et al., 2022) [312] Melittin derived
CancerBEAS-2B, RBL-2h3, Raw264.7, HeLa cell linesAnti-inflammatory
Allergy
Cytotoxicity
(Nguyen, Yoo, An et al., 2022) [51]BV Animal: mice
Injection
Microneedle delivery of BV
Anti-inflammatory
Neuroprotection
(J.-Y. Kim, Lee et al., 2020) [52]BV
(Apis m.)
Acute kidney injuryAnimal: mice
Injection
Anti-apoptotic
Anti-inflammatory
Oxidative stress
(Orrù et al., 2025) [431] BV
(Apis m.)
DPPH assay
(Mirzavi et al., 2024) [56]BV (honeybee)Colon cancerAnimal: mice
Injection
Xenograft
C26 cell line
Anti-inflammatory
Anti-tumor
Gene expression-pathway
(Senturk et al., 2022) [95]BV
(Apis m.)
Animal: rats
Injection
Anti-inflammatory
Oxidative stress
Skeletal muscle, Liver
(Qanash et al., 2025) [322] BV
(Apis m.)
Cancer HePG2 Cell lineAnti-inflammatory, Cytotoxicity, Nanoparticle: Zinc oxide and polyvinyl alcohol
(Lomeli-Lepe et al., 2025) [101] BV Acupoint injection
Animal: mice
Neuroprotection
(J. Yao, Li et al., 2025) [288] Not just melittin CancerAnimal: rats
Topical administration
NIH, RAW264.7 cell lines
Synergy with Cu2+
skin diseases, ROS
Table 13. Experimental design of articles.
Table 13. Experimental design of articles.
Main FocusNumber of Studies
In VivoIn VitroIn SilicoClinicalIn Vivo and In Vitro
Anti-inflammatory622922NA
Immunomodulatory272410NA
Anti-microbial---0177
Anti-cancer5012710NA
Anti-oxidant17901NA
NA, not applicable.
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Erdoğan, P.M.; Bilgili-Tetikoğlu, F.; Çelik-Uzuner, S.; Yıldız, O.; Kolayli, S.; Mossialos, D. Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review. Molecules 2025, 30, 4003. https://doi.org/10.3390/molecules30194003

AMA Style

Erdoğan PM, Bilgili-Tetikoğlu F, Çelik-Uzuner S, Yıldız O, Kolayli S, Mossialos D. Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review. Molecules. 2025; 30(19):4003. https://doi.org/10.3390/molecules30194003

Chicago/Turabian Style

Erdoğan, Perihan Mutlu, Funda Bilgili-Tetikoğlu, Selcen Çelik-Uzuner, Oktay Yıldız, Sevgi Kolayli, and Dimitris Mossialos. 2025. "Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review" Molecules 30, no. 19: 4003. https://doi.org/10.3390/molecules30194003

APA Style

Erdoğan, P. M., Bilgili-Tetikoğlu, F., Çelik-Uzuner, S., Yıldız, O., Kolayli, S., & Mossialos, D. (2025). Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review. Molecules, 30(19), 4003. https://doi.org/10.3390/molecules30194003

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