Pharmaceuticals

13 pages, 1124 KB

Open AccessArticle

Preliminary Data Regarding the Potential of Oxytocin to Modulate Aggressive Behaviour in a VPA-Based Animal Model of Autism Spectrum Disorder

by Oana-Georgiana Oprea, Petru Fabian Lungu, Alexandru Ionut Chelaru, Ioana-Miruna Balmus, Roxana Strungaru-Jijie, Gabriel Plavan, Mircea Nicusor Nicoara, Alin Ciobica, Diana Gheban and Stefan Chiriac

Pharmaceuticals 2026, 19(2), 343; https://doi.org/10.3390/ph19020343 - 23 Feb 2026

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Abstract

Background/Objectives: Aggressive behaviour is commonly associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD), and could be understood as a response to daily stress routines, which negatively impacts patients’ quality of life. Oxytocin (OT), a neuropeptide involved in social bonding and [...] Read more.

Background/Objectives: Aggressive behaviour is commonly associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD), and could be understood as a response to daily stress routines, which negatively impacts patients’ quality of life. Oxytocin (OT), a neuropeptide involved in social bonding and socio-affective regulation, has emerged as a promising candidate to enrich, rather than replace, current pharmacological approaches in managing ASD-associated aggressive behaviour. In this study, we examined the potential of OT to modulate aggressive behaviour frequency in a VPA-based animal model of ASD. Methods: Sixty adult zebrafish (1:1 sex ratio) were divided into six groups (n = 10/group) and received the following treatment for 7 consecutive days: CTR—control (no treatment); VPA (28.8 mg/L valproic acid); OT (33.2 ng/mL oxytocin); RIS (170 μg/L risperidone); VPA + OT (28.8 mg/L valproic acid and 33.2 ng/mL oxytocin); and VPA + RIS (28.8 mg/L valproic acid and 170 μg/L risperidone). The locomotor performance, and socio-affective and aggressive behaviours, were measured in the Novel Tank and Mirror Biting tests at the end of the treatments. Results: We observed that the VPA treatment led to locomotion and socio-affective impairments, as well as aggressive behaviour. Also, we found that OT and RIS had comparable potential to modulate the frequency of aggressive and anxiety-like behaviours. Conclusions: Our preliminary data showed that OT has the potential to modulate the frequency of anxiety-like and aggressive behaviours, similarly to the atypical antipsychotic, RIS, in our VPA zebrafish model. However, further studies are needed to investigate the mechanisms of action and their potential synergistic effects. Full article

(This article belongs to the Special Issue Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD))

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17 pages, 4422 KB

Open AccessArticle

Novel Propofol Analogs: Design, Synthesis and Evaluation of Dihydrobenzofuran Derivatives as General Anesthetics

by Jun-Jie Shi, Jia-Quan Feng, Yuan-Hai Zou, Yan Huo, Shi-Han Ma, Xiao-Jing He, Ze-Hong Wan, Xiang-Qing Xu, Zhi-Jing Hu, Yi-Long Shi, Jin-Hui Wu and Xiang-Yang Xu

Pharmaceuticals 2026, 19(2), 342; https://doi.org/10.3390/ph19020342 - 22 Feb 2026

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Abstract

Background: Propofol is used worldwide as a short-acting intravenous anesthetic in clinical practice; however, side effects such as injection pain and respiratory depression remain clinically relevant. Therefore, identification of safer propofol analogs is required. Method: In response to the urgent need [...] Read more.

Background: Propofol is used worldwide as a short-acting intravenous anesthetic in clinical practice; however, side effects such as injection pain and respiratory depression remain clinically relevant. Therefore, identification of safer propofol analogs is required. Method: In response to the urgent need for optimized potency and reduced side effects, a series of dihydrobenzofuran derivatives were designed as expectedly better propofol analogs through conformational restriction. A loss of righting reflex assay was conducted to evaluate the sedative/anesthetic properties of the synthesized compounds, and a respiratory depression test was performed for safety assessment. Results: Most of the designed compounds were shown to possess promising anesthetic properties as propofol analogs. The represented 53A had higher potency and a wider safety margin (ED₅₀:3.898 vs. 8.040 mg/kg in mice; 2.985 vs. 5.894 mg/kg in rats; TI (therapeutic index): 6.172 vs. 5.061 in mice; 4.362 vs. 2.580 in rats) than propofol, and fast onset and recovery times were maintained. The phosphate prodrug 56A also exhibited better efficiency and safety than fospropofol, along with a longer duration and faster recovery time in sedative profiles. Furthermore, alleviation of the adverse effects of respiratory depression has been demonstrated. Conclusions: 53A has the potential to be selected as a preclinical candidate for clinical development. Full article

(This article belongs to the Section Medicinal Chemistry)

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19 pages, 2945 KB

Open AccessArticle

A Comparative Evaluation of the Therapeutic Effects of Adenosine Triphosphate, Coenzyme Q10, Pyridoxine, and Thiamine Pyrophosphate in a Linezolid-Induced Peripheral Neuropathic Pain Model in Rats

by Habip Burak Ozgodek, Ramazan Ince, Agah Abdullah Kahramanlar, Bulent Yavuzer, Esra Tuba Sezgin, Renad Mammadov, Nuri Bakan and Halis Suleyman

Pharmaceuticals 2026, 19(2), 341; https://doi.org/10.3390/ph19020341 - 22 Feb 2026

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Abstract

Background/Objectives: Linezolid is an oxazolidinone antibiotic whose prolonged use is associated with peripheral neuropathy, hyperlactatemia, and metabolic acidosis. These adverse effects are primarily linked to the inhibition of mitochondrial protein synthesis, respiratory chain dysfunction, and oxidative stress. Given the central role of impaired [...] Read more.

Background/Objectives: Linezolid is an oxazolidinone antibiotic whose prolonged use is associated with peripheral neuropathy, hyperlactatemia, and metabolic acidosis. These adverse effects are primarily linked to the inhibition of mitochondrial protein synthesis, respiratory chain dysfunction, and oxidative stress. Given the central role of impaired energy metabolism and redox imbalance in drug-induced peripheral neuropathy, therapeutic strategies targeting mitochondrial function are of particular interest. Accordingly, this study aimed to comparatively evaluate the effects of adenosine triphosphate (ATP), coenzyme Q10 (CoQ10), pyridoxine, and thiamine pyrophosphate (TPP) on linezolid-induced peripheral neuropathic pain in rats. Methods: Sixty male albino Wistar rats were assigned to ten groups: healthy (HG); ATP-only (ATPG, 5 mg/kg, intraperitoneally); CoQ10-only (CQ10G, 10 mg/kg, orally); pyridoxine-only (PDXG, 50 mg/kg, orally); TPP-only (TPPG, 20 mg/kg, intraperitoneally); linezolid-only (LZDG, 125 mg/kg, orally); linezolid+ATP (ATLG); linezolid+CoQ10 (CQLG); linezolid+pyridoxine (PXLG); and linezolid+TPP (TPLG). Treatments were administered once daily for ATP, CoQ10, and TPP, and twice daily for linezolid and pyridoxine for 14 days. Oxidative stress indices (MDA, tGSH, SOD, CAT) were quantified in the sciatic nerve using ELISA. Serum lactate dehydrogenase (LDH) activity and blood lactate levels were determined to evaluate metabolic disturbances. Mechanical paw withdrawal thresholds were measured using the Randall–Selitto test both before and after treatment. Results: Linezolid significantly reduced paw withdrawal thresholds and induced oxidative stress, antioxidant depletion, increased LDH activity, and hyperlactatemia. Co-treatment with ATP and CoQ10 attenuated oxidative stress but did not significantly improve linezolid-induced reductions in nociceptive thresholds. In contrast, pyridoxine partially alleviated linezolid-induced neuropathic pain and improved biochemical parameters. Notably, TPP exerted the most robust protective effect, preserving nociceptive thresholds and effectively normalizing oxidative stress and metabolic indices. Conclusions: These findings identify TPP as a promising therapeutic strategy for mitigating linezolid-induced peripheral neuropathic pain by targeting mitochondrial energy metabolism and pyruvate–lactate homeostasis. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Strategies for Drug Addiction and Medication-Induced Toxicity)

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41 pages, 484 KB

Open AccessReview

Biological Treatment of Psoriasis—Data So Far

by Mateusz Matwiejuk, Agnieszka Mikłosz, Hanna Myśliwiec, Adrian Chabowski and Iwona Flisiak

Pharmaceuticals 2026, 19(2), 340; https://doi.org/10.3390/ph19020340 - 21 Feb 2026

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Abstract

Psoriasis is a chronic, inflammatory skin disease occurring worldwide that significantly affects patients’ quality of life. This common skin condition is characterized by abnormal hyperplasia of keratinocytes, which leads to the formation of raised, scaly plaques, typically located on the head, elbows, knees, [...] Read more.

Psoriasis is a chronic, inflammatory skin disease occurring worldwide that significantly affects patients’ quality of life. This common skin condition is characterized by abnormal hyperplasia of keratinocytes, which leads to the formation of raised, scaly plaques, typically located on the head, elbows, knees, and lumbar region. Psoriasis usually requires long-term drug therapy, which aims not only to combat skin symptoms but also to improve quality of life. Although topical treatments, systemic treatments (methotrexate, cyclosporine, acitretin), and phototherapy play a role, biologic agents have improved the efficacy of treatment of moderate-to-severe psoriasis. The purpose of this article is to comprehensively review the clinical trial data and evaluate and compare the key features of the currently approved biologic drugs for the treatment of psoriasis. Full article

(This article belongs to the Special Issue Research Advances in Targeted Therapy for Facial Skin Diseases)

19 pages, 1769 KB

Open AccessArticle

Adaptogenic and Neuroprotective Effects of the Thai Herbal Formula AYW-KK-04 Against Chronic Stress-Induced Cognitive Impairment

by Pathomporn Saisud, Orawan Monthakantirat, Prathan Luecha, Suppachai Tiyaworanant, Abdulwaris Mading, Yutthana Chotritthirong, Sunanthra Ruangrit, Nawarat Jintanamaneerat, Jarurat Trakanchan, Juthamart Maneenet, Suresh Awale and Yaowared Sumanont

Pharmaceuticals 2026, 19(2), 339; https://doi.org/10.3390/ph19020339 - 21 Feb 2026

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Abstract

Background/Objectives: Unpredictable chronic mild stress exposure is a primary driver of cognitive decline, largely mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation and subsequent oxidative neurotoxicity. In traditional Thai medicine, the AYW-KK-04 formulation—a complex polyherbal remedy—has long been utilized as a “Ya Aayu-Wattana” to restore [...] Read more.

Background/Objectives: Unpredictable chronic mild stress exposure is a primary driver of cognitive decline, largely mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation and subsequent oxidative neurotoxicity. In traditional Thai medicine, the AYW-KK-04 formulation—a complex polyherbal remedy—has long been utilized as a “Ya Aayu-Wattana” to restore vitality and elemental balance, yet its neurobiological mechanisms remain poorly understood. This study aimed to evaluate the adaptogenic and neuroprotective potential of AYW-KK-04 against cognitive impairment. Methods: Unpredictable Chronic Mild Stress (UCMS)-induced cognitive impairment in a ICR mouse model. Total phenolic and flavonoid contents and antioxidant capacity (ABTS assay) of AYW-KK-04 were determined. Behavioral assessments using Y-maze test, novel object recognition test (NORT), and Morris Water Maze (MWM) test. BDNF, CREB, Nrf and Keap1 mRNA gene expression, SOD and CAT enzymatic activity and lipid peroxidation assay were investigated to clarify the mechanisms of action. Moreover, HPLC chromatography was studied to quantify the active compounds of the AYW-KK-04 formulation. Results: It demonstrated that oral administration of AYW-KK-04 significantly reversed UCMS-induced memory deficits. At the molecular level, AYW-KK-04 effectively upregulated BDNF and CREB mRNA expression in the frontal cortex and hippocampus, suggesting a restoration of synaptic plasticity. Simultaneously, the formulation activated the Nrf2/Keap1 signaling pathway, leading to enhanced SOD and CAT enzymatic activities and a marked reduction in MDA-mediated lipid peroxidation. HPLC analysis confirmed the presence and consistency of key bioactive constituents. Conclusions: These findings suggest that the adaptogenic properties of AYW-KK-04 arise from its dual capacity to reinforce neurotrophic support and bolster the endogenous antioxidant shield, providing a mechanistic support for the traditional use of AYW-KK-04 as an adaptogenic formulation and highlighting its potential as a multi-target intervention for stress-related cognitive dysfunction. Full article

(This article belongs to the Section Natural Products)

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41 pages, 5770 KB

Open AccessReview

Azole–Flavonoid Hybrids as Emerging Anticancer Agents: A Bioactivity-Focused Review

by Mihaela Lipovanu, Anca Miron, Nina Filip, Cristina Elena Horhogea and Ana Clara Aprotosoaie

Pharmaceuticals 2026, 19(2), 338; https://doi.org/10.3390/ph19020338 - 20 Feb 2026

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Abstract

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to [...] Read more.

Despite notable progress in drug discovery, cancer treatment remains hindered by limited therapeutic efficacy, poor target specificity, adverse effects, and the development of drug resistance. Molecular hybridization, which integrates two or more bioactive entities into a single molecule, has shown considerable potential to overcome these limitations. Since both azoles and flavonoids have demonstrated anticancer potential, extensive studies have been undertaken to combine the two entities and enhance the bioactivity of the resulting hybrids. In this context, numerous azole–flavonoid hybrids have been synthesized and investigated for their anticancer potential. This review provides an overview of the azole–flavonoid hybrids that are promising candidates for novel anticancer drug development, highlighting their superior antitumor potency compared to reference drugs, multitarget activity, tumor-selective cytotoxicity, efficacy against drug-resistant tumor cells, and structure–activity relationships. The review covers 250 hybrids, primarily triazole–chalcone hybrids but also triazole–flavone, flavanone, flavonol, and isoflavone hybrids, as well as other azole–flavonoid hybrids (imidazole–, pyrazole–, isoxazole–, and thiazole–flavonoid hybrids). Full article

(This article belongs to the Special Issue Hybrid and Chimeric Heterocycles: A Promising Approach to Synthesizing Biologically Active Compounds)

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26 pages, 6312 KB

Open AccessArticle

Identification of Novel Extracellular-Signal-Regulated Kinase 2 Inhibitors Through Machine Learning-Driven De Novo Design, Molecular Docking, and Free-Energy Perturbation

by Ibrahim A. Alsarra, Mahima Sudhir Kolpe and Md Ataul Islam

Pharmaceuticals 2026, 19(2), 337; https://doi.org/10.3390/ph19020337 - 20 Feb 2026

Viewed by 254

Abstract

Background: The extracellular-signal-regulated kinase (ERK) cascade regulates cell proliferation, differentiation, and survival, and ERK2 mediates substrate phosphorylation, influencing gene expression and cellular functions. Methods: In the current study, a pool of new molecules was generated using the DeLA-Drug, a machine learning [...] Read more.

Background: The extracellular-signal-regulated kinase (ERK) cascade regulates cell proliferation, differentiation, and survival, and ERK2 mediates substrate phosphorylation, influencing gene expression and cellular functions. Methods: In the current study, a pool of new molecules was generated using the DeLA-Drug, a machine learning (ML)-assisted de novo design tool. The chemical space was reduced through a similarity search against active ERK2 inhibitors and molecular docking with AutoDock vina, followed by pharmacokinetic assessment in DeepPK. Poses of the final selected molecules were refined in DiffDock, and dynamicity was assessed through molecular dynamics (MD) simulation. Finally, the free-energy perturbation (FEP)-based binding affinity was explored in Gromacs2023.4. Results: From the above approaches, four molecules (Ek1, Ek2, Ek3, and Ek4) were identified as promising candidates with favorable binding interactions. Molecular docking revealed that the selected molecules exhibited higher binding affinity for ERK2, ranging from −9.50 to −10.50 kcal/mol. The dynamics assessment via MD simulation clearly revealed their strong association with ERK2, corroborated by the lower deviation of the ERK2 backbone in dynamic states. All four screened molecules have satisfactory pharmacokinetic properties, medicinal chemistry properties, and good synthetic accessibility scores, indicating their potential as drug-like compounds under Lipinski’s rule of five to inhibit or modulate ERK2 activity. The FEP energy of Ek1 was found to be −26.85 kJ/mol, which is higher than the standard molecule (−22.77 kJ/mol) and indicates its strong affinity toward ERK2. Conclusions: These results suggest that all proposed ERK2 modulators are potential avenues for future drug discovery targeting ERK2, subject to experimental validation. Full article

(This article belongs to the Section AI in Drug Development)

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21 pages, 352 KB

Open AccessReview

The Genetic Mosaic of Depression: Linking Polymorphisms to Neuroplasticity and Stress Regulation

by Aneta Bednářová, Emma Szilassyová, Dominika Jarčušková, Daniel Múdry and Terézia Kisková-Šimková

Pharmaceuticals 2026, 19(2), 336; https://doi.org/10.3390/ph19020336 - 20 Feb 2026

Viewed by 228

Abstract

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review [...] Read more.

The origins of major depressive disorder (MDD) are complex, involving both environmental influences and a substantial genetic contribution. Genetic polymorphisms have been implicated in modulating susceptibility, disease course, and treatment response, yet findings are often modest, population-dependent, and sometimes inconsistent. This narrative review synthesizes current evidence on genetic variants associated with MDD, highlighting well-replicated results while distinguishing exploratory or emerging findings. Key systems reviewed include serotonergic (SLC6A4), neurotrophic (BDNF rs6265 and rs962369), dopaminergic and stress-response pathways (COMT, FKBP5, CRHR1), as well as additional emerging genes such as MAOA, TPH2, and FTO. We evaluate these variants in the context of their biological relevance, including neuroplasticity, neurotransmission, and hypothalamic–pituitary–adrenal (HPA) axis regulation, and discuss how polygenic and epigenetic interactions may shape clinical heterogeneity. This framework not only integrates current genetic knowledge but also outlines potential translational applications, offering perspectives for personalized approaches to diagnosis, prognosis, and treatment in MDD. Full article

(This article belongs to the Special Issue New Trends in the Treatment of Neuropsychiatric Disorders)

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17 pages, 3734 KB

Open AccessArticle

Synergistic Enhancement of Peripheral Nerve Regeneration via Ibudilast-Primed Three-Dimensional Spheroid Culture of Human Adipose-Derived Stem Cells

by Ji Young Bang and Nam-Kyu Lim

Pharmaceuticals 2026, 19(2), 335; https://doi.org/10.3390/ph19020335 - 20 Feb 2026

Viewed by 245

Abstract

Background: Peripheral nerve regeneration relies on Schwann cell activation and neurotrophic support. Although adipose-derived stem cells (ADSCs) show therapeutic potential through paracrine mechanisms, their clinical application is often limited by donor-dependent heterogeneity in therapeutic efficacy. Accordingly, strategies to standardize and potentiate their [...] Read more.

Background: Peripheral nerve regeneration relies on Schwann cell activation and neurotrophic support. Although adipose-derived stem cells (ADSCs) show therapeutic potential through paracrine mechanisms, their clinical application is often limited by donor-dependent heterogeneity in therapeutic efficacy. Accordingly, strategies to standardize and potentiate their secretory function are essential. This study investigated a safety-optimized strategy to achieve this by combining three-dimensional (3D) spheroid culture with ibudilast, a clinically approved phosphodiesterase inhibitor. Methods: Human ADSCs were cultured in 2D or 3D conditions with varying ibudilast concentrations. Safety was confirmed via CCK-8 assays, and trophic factor secretion was quantified by RT-qPCR and ELISA. To rigorously validate functional outcomes, conditioned media were applied to a dual-model system comprising immortalized rat (RSC96) and primary human Schwann cells (HSwCs), assessing migration and the expression of regeneration-associated genes. Results: Ibudilast demonstrated no cytotoxicity. While 3D culture alone enhanced secretion compared to 2D controls, the addition of ibudilast provided a synergistic boost, resulting in a 6- to 14-fold increase in NGF, VEGF, and IGF-1 levels compared to 3D spheroids alone. Notably, conditioned media from these primed spheroids significantly accelerated HSwCs migration and induced robust upregulation of myelination-related genes (specifically PMP22 and EGR2), with trophic effects sustained for up to 72 h. Conclusions: Ibudilast-primed 3D spheroids synergistically amplify the neuroregenerative secretome of ADSCs. By utilizing a repurposed, safe small molecule to overcome functional variability and maximize potency without genetic manipulation, this strategy represents a highly translatable candidate for peripheral nerve repair. Full article

(This article belongs to the Section Biopharmaceuticals)

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21 pages, 905 KB

Open AccessSystematic Review

Artificial Intelligence for Drug Safety Across the Lifecycle and Decision Type: A Scoping Review

by Tae Woo Kim, Sihyeon Park and Miryoung Kim

Pharmaceuticals 2026, 19(2), 334; https://doi.org/10.3390/ph19020334 - 19 Feb 2026

Viewed by 410

Abstract

Background/Objectives: Artificial intelligence (AI) is increasingly applied to drug safety evaluation, yet evidence is dispersed across lifecycle stages and tasks. This scoping review aimed to (1) map how AI supports safety- and treatment-related decision types across the drug lifecycle, and (2) examine [...] Read more.

Background/Objectives: Artificial intelligence (AI) is increasingly applied to drug safety evaluation, yet evidence is dispersed across lifecycle stages and tasks. This scoping review aimed to (1) map how AI supports safety- and treatment-related decision types across the drug lifecycle, and (2) examine evaluation strategies used to assess model reliability for clinical or regulatory use. Methods: Using Arksey and O’Malley’s framework, we searched a major database for studies published in the past decade that applied AI or machine learning to drug safety or medication-related decisions. After screening, we extracted data on lifecycle stage, decision type, AI methods, data sources, and evaluation strategies. A lifecycle–decision matrix was constructed to characterize application patterns. Results: AI applications were concentrated in real-world clinical care × patient-level safety prediction and post-marketing × safety surveillance, using EHRs, spontaneous reporting systems, and clinical text. Common methods included gradient boosting, deep neural networks, graph neural networks, and natural language processing models. This concentration reflects structural incentives favoring safety-oriented applications with readily available data and lower decision liability. Evidence for treatment optimization, regulatory decision modeling, and evidence synthesis was limited. Most studies used internal validation; external validation and real-world deployment were uncommon, indicating early methodological maturity and limited translational readiness. Conclusions: AI demonstrates strong potential to enhance drug safety—particularly in risk prediction and pharmacovigilance—but its use remains uneven across the lifecycle. By situating AI applications within explicit lifecycle stages and decision contexts, this review clarifies where progress has advanced, where translation has stalled, and why these gaps persist. Limited external validation and minimal real-world testing constrain clinical and regulatory adoption. These findings suggest that external validation and real-world testing may contribute to further advances in AI for drug safety. Full article

(This article belongs to the Section Pharmacology)

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33 pages, 6027 KB

Open AccessReview

Metal-Functionalized Nanozymes in Antibacterial Wound Management: Recent Advances and Future Perspectives

by Selvam Sathiyavimal, Devaraj Bharathi and Ezhaveni Sathiyamoorthi

Pharmaceuticals 2026, 19(2), 333; https://doi.org/10.3390/ph19020333 - 19 Feb 2026

Viewed by 433

Abstract

Chronic and infected wounds continue to pose significant clinical challenges due to microbial infections, biofilm development, inflammation, and poor tissue regeneration. Traditional antibiotics medications often show low efficacy and lack stability. The demand for new therapeutic approaches is increasing due to bacterial resistance. [...] Read more.

Chronic and infected wounds continue to pose significant clinical challenges due to microbial infections, biofilm development, inflammation, and poor tissue regeneration. Traditional antibiotics medications often show low efficacy and lack stability. The demand for new therapeutic approaches is increasing due to bacterial resistance. Metal-based nanozymes have intrinsic enzyme-like catalytic activity and emerged as a promising class of antibacterial agents for wound-healing applications. The functionalization with metals such as silver (Ag), copper (Cu), iron (Fe), manganese (Mn), cerium (Ce), platinum (Pt) and gold (Au) enhances peroxidase (POD)-, oxidase (OXD)-, and catalase (CAT)-like biomimetic activities. This improvement enables efficient reactive oxygen species (ROS) production, biofilm inhibition, and microenvironment-responsive antibacterial activity. These metal-nanozymes also alter the immune response, increase angiogenesis, and promote extracellular matrix remodeling when combined with metals and also polysaccharides. This review summarizes recent advances in metal-incorporated antibacterial nanozymes including their design, catalytic mechanisms, structure–activity relationships, and integration into hydrogels, films, and fibers for wound healing. Key challenges such as biosafety, metal ion release, the inflammatory balance, and clinical translation are critically discussed. Emerging directions such as single-atom nanozymes, cascade enzyme systems, and stimuli-responsive platforms are highlighted as promising routes for next-generation wound therapeutics. Overall, this review underscores the clinical potential of metal-functionalized nanozymes for infected wound management; however, concerns regarding ion leakage and long-term safety persist emphasizing the need for controlled designs and biocompatible systems to enable safe translation. Full article

(This article belongs to the Special Issue Challenges in Discovering Innovations Related to Biofilms: Virulence, Spread, Control Strategies and Treatment)

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27 pages, 5762 KB

Open AccessArticle

Comprehensive Investigation of a Novel Schiff Base: Synthesis, Anticancer Efficacy, Gene Expression Profiling, and Computational Analyses

by Tugba Agbektas, Özhan Pazarcı, Ayca Tas, Alakbar Huseynzada, Ruslan Guliyev, Ulviyya Hasanova, Emre Can Buluz, Savas Kaya, Alejandro Morales-Bayuelo and Yavuz Silig

Pharmaceuticals 2026, 19(2), 332; https://doi.org/10.3390/ph19020332 - 18 Feb 2026

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Abstract

(1) Background: This study evaluates the anticancer potential of a newly synthesized azomethine-based compound, 6,6′,5,8-Dioxa-2,11-diazadodeca-1,11-diene-1,12-diyl)bis(4-bromo-2-methoxyphenol) (B-134-0), against osteosarcoma (SAOS-2) cells, focusing on its effects on apoptosis and DNA-damage-related gene expression. (2) Methods: B-134-0 was synthesized via condensation and tested at eight concentrations (0.5–100 [...] Read more.

(1) Background: This study evaluates the anticancer potential of a newly synthesized azomethine-based compound, 6,6′,5,8-Dioxa-2,11-diazadodeca-1,11-diene-1,12-diyl)bis(4-bromo-2-methoxyphenol) (B-134-0), against osteosarcoma (SAOS-2) cells, focusing on its effects on apoptosis and DNA-damage-related gene expression. (2) Methods: B-134-0 was synthesized via condensation and tested at eight concentrations (0.5–100 μg/mL) for 24, 48, and 72 h. Cytotoxicity was assessed through MTT assay, and gene expression levels of TP53, RAD51, BRCA2, CASP2, MYC, MDM2, CDKN1A, ERCC1, ATR, and PRKDC were quantified through qPCR using the ΔΔ_Ct method. Molecular docking and DFT analyses were performed to explore structural stability and protein interactions. (3) Results: B-134-0 exhibited strong time-dependent cytotoxicity (IC₅₀: 71.58, 54.36, and 12.59 μg/mL at 24, 48, and 72 h, respectively) and significantly modulated the expression of cell cycle and DNA-repair-associated genes. The compound notably downregulated TP53, RAD51, CASP2, MYC, and MDM2, while CDKN1A and BRCA2 showed relative upregulation, indicating activation of the DNA damage response. Docking results revealed strong binding affinity with BRCA2 and CDKN1A, consistent with experimental findings. (4) Conclusions: These results indicate that B-134-0 exhibits potent anticancer activity by modulating DDR and apoptosis pathways, with strong molecular stability, suggesting its promise as a therapeutic candidate for osteosarcoma. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs: 2nd Edition)

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48 pages, 17329 KB

Open AccessArticle

Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer

by Konstantinos E. Alifieris, Panagiotis Dalezis, Sofia Sagredou, Ioanna A. Anastasiou, Maria Deligiorgi, Christos Siokatas, Nikolaos Spanakis, Konstantinos Almpanakis, Maria Voura, Kyriakos Orfanakos, Mihalis Panayiotidis, Vasiliki Sarli and Dimitrios T. Trafalis

Pharmaceuticals 2026, 19(2), 331; https://doi.org/10.3390/ph19020331 - 17 Feb 2026

Viewed by 482

Abstract

Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel [...] Read more.

Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel hybrid homo-aza (lactam) steroidal antimetabolites (GE23, CS18, CS23, KA44, MV16) were synthesized and tested against three pancreatic and four colorectal carcinoma cell lines with distinct molecular characteristics. Antiproliferative activity (MTT), apoptosis (Annexin V/PI), and cell cycle effects were assessed. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition was examined via molecular docking, Western blot, and enzymatic assays. Correlations between docking binding scores (DBS) and biological data were analyzed, and effects were compared with reference drugs (5-FU, MTX, GEM). Results: CS23, CS18, and KA44 exhibited the most potent cytostatic activity (mean GI₅₀ 10–80 µM). CS23 also induced high cytocidal effects, strong apoptosis (40% at 72 h), and G1/S arrest. Moreover, docking predicted the high binding affinity of CS23 for both TS (−11.2 kcal/mol) and DHFR (−11.5 kcal/mol), which was validated by Western blot and enzymatic inhibition (IC₅₀ ≈ 20 nM). Correlation analyses showed significant relationships between hybrid steroidal antimetabolites’ cytostatic efficacy and DBS for TS (r = −0.75) and DHFR (r = −0.76), and combined DBS values predicted growth inhibition (r = −0.81, p < 0.01). No simple, universal correlation with single mutations of KRAS, BRAF, PI3K, or TP53 was found. Conclusions: Lactam steroidal antimetabolite hybrids, particularly CS23, act as dual TS/DHFR inhibitors, inducing apoptosis and cell cycle arrest with improved selectivity. Their strong in silico–in vitro concordance provides a compelling preclinical rationale for further evaluation of steroidal antimetabolites as next-generation therapeutics for resistant gastrointestinal malignancies. Full article

(This article belongs to the Special Issue Advances in Hybrid Anticancer Drugs: Innovations and Therapeutic Potential)

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28 pages, 1049 KB

Open AccessReview

Cannabidiol in Neurology: Current Insights and Translational Perspectives

by Magdalena Białoń, Marta Kędziora and Katarzyna Starowicz

Pharmaceuticals 2026, 19(2), 330; https://doi.org/10.3390/ph19020330 - 17 Feb 2026

Viewed by 278

Abstract

Cannabidiol (CBD) is one of the most studied compounds of Cannabis sativa and has attracted significant interest due to its therapeutic and beneficial properties, which have been confirmed in numerous preclinical and clinical studies over the last few years. A great advantage of [...] Read more.

Cannabidiol (CBD) is one of the most studied compounds of Cannabis sativa and has attracted significant interest due to its therapeutic and beneficial properties, which have been confirmed in numerous preclinical and clinical studies over the last few years. A great advantage of CBD over the other widely known Cannabis sativa ingredient, Δ-9-tetrahydrocannabinol (THC), is that CBD does not exert intoxicating and psychoactive effects, making it an attractive candidate for therapeutic applications in neurological disorders. CBD has been shown to exert antioxidant, analgesic, anti-inflammatory, and neuroprotective effects, with therapeutic potential for various neurological conditions. To date, the only drug that consists solely of highly purified CBD is Epidiolex, which is used in the management of severe forms of epilepsy such as Dravet syndrome and Lennox–Gastaut syndrome. Another legal medication containing CBD (albeit with the addition of THC) is Sativex, used to alleviate spasticity in multiple sclerosis. Besides epilepsy, preclinical data suggest that CBD alone may be potentially beneficial in treating chronic pain, multiple sclerosis, Alzheimer’s and Parkinson’s diseases, or stroke. The safety profile of CBD is generally considered favorable, as the most commonly reported adverse effects are mild (e.g., somnolence, diarrhea). However, much attention should be paid as CBD-driven drug–drug interactions have been reported. This review article aims to assess the outcomes of preclinical and clinical research on CBD’s effects in various neurological conditions while also addressing potential risks and concerns related to its use. Full article

(This article belongs to the Special Issue The Therapeutic Potential of Cannabidiol)

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22 pages, 2178 KB

Open AccessArticle

Involvement of Serotonergic and Dopaminergic Systems in Aloysia gratissima var. gratissima: Antidepressant-like Effect, UPLC-DAD-MS Chemical Characterization, and Computational Evidence

by Miguel A. Campuzano-Bublitz, Alberto Burgos-Edwards, Elvio Gayozo, Adelian A. Acosta, Rodrigo S. Paredes, Alex D. Campuzano-Kennedy, Antonia K. Galeano, Yenny P. González, Nelson L. Alvarenga, Teresa Taboada-Jara and María L. Kennedy

Pharmaceuticals 2026, 19(2), 329; https://doi.org/10.3390/ph19020329 - 17 Feb 2026

Viewed by 507

Abstract

Background/Objectives: As the prevalence of depression and the use of antidepressants have risen steadily in the last decade, new treatment options are needed. Aloysia gratissima var. gratissima ethanol extract has previously shown antidepressant-like activity, and the present study was conducted to identify the [...] Read more.

Background/Objectives: As the prevalence of depression and the use of antidepressants have risen steadily in the last decade, new treatment options are needed. Aloysia gratissima var. gratissima ethanol extract has previously shown antidepressant-like activity, and the present study was conducted to identify the active fraction and clarify the possible mechanisms of action. Methods: Tail suspension (TST) and forced swimming (FST) behavioral tests were performed, and possible mechanisms of action were elucidated using serotonergic, dopaminergic, adrenergic, and GABAergic system antagonists. UPLC-DAD-MS analyses were performed to identify compounds in active fractions, and molecular docking studies were carried out to determine the binding affinities of these compounds to serotonergic and dopaminergic receptors (5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R). Results: Ethyl acetate and butanol fractions were found to decrease immobility time in FST. The reduction in immobility time during the FST caused by the ethyl acetate fraction was reversed by pretreating mice with WAY100635 (5-HT_1A antagonist), ketanserin (a 5-HT_2A antagonist, ondansetron (5-HT₃ antagonist), or haloperidol (D₂ antagonist). UPLC-DAD-MS analysis revealed a similar composition for the ethyl acetate and butanol fractions of A. gratissima var. gratissima. Pharmacokinetic predictions suggest that only a few of the identified compounds have the potential to permeate the blood–brain barrier, and molecular docking simulations showed that compounds such as 13-oxooctadecadienoic acid, ferulic acid, and coumaric acid have binding affinities to the druggable site of serotonergic and dopaminergic receptors. Conclusions: These results suggest that the Agg ethyl acetate fraction possesses antidepressant-like activities, altering dopaminergic and serotonergic system functions. Computational simulations also suggest that some of the identified compounds have binding affinities to the 5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R receptors. Full article

(This article belongs to the Special Issue Neuropharmacology of Plant Extracts and Their Active Compounds (Second Edition))

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19 pages, 1004 KB

Open AccessArticle

Chinese Expert Consensus for the Application of rh-aFGF for Chronic Refractory Wounds

by Junli Zhou, Xuanru Zhu, Dongcheng Ye, Xiaobing Fu, Yuesheng Huang and Professional Committee of Wound Repair of Chinese Medical Doctor Association

Pharmaceuticals 2026, 19(2), 328; https://doi.org/10.3390/ph19020328 - 17 Feb 2026

Viewed by 363

Abstract

Background and Objective: Chronic refractory wounds not only persist and delay healing, causing physical and mental suffering to patients and reducing their quality of life but also impose a heavy burden on their families and society. Recombinant human acidic fibroblast growth factor (rh-aFGF), [...] Read more.

Background and Objective: Chronic refractory wounds not only persist and delay healing, causing physical and mental suffering to patients and reducing their quality of life but also impose a heavy burden on their families and society. Recombinant human acidic fibroblast growth factor (rh-aFGF), approved in China for decades, is a growth factor with multiple biological effects which can promote the healing of various wounds. It is crucial to develop an rh-aFGF expert consensus for standardizing the clinical application of aFGF and enhancing its clinical value. Methods: The literature related to rh-aFGF, including clinical trials, experimental research, and reviews, was collected and selected from PubMed, Web of Science, Medline, CNKI, and the Wangfang database. The expert recommendations were formed by a combination of clinical research quality, use of the Delphi questionnaire, and consensus reached during meetings involving experts. Results: A total of 12 consensus recommendations for clinical application of rh-aFGF on chronic refractory wounds (CRWs) were successfully formulated, of which seven strong, four moderate, and one weak recommendations were suitable for various clinical sets. The recommendations include specifications for duration of rh-aFGF treatment, dosage, types of wounds, and its combination with other products and dressings. Conclusions: rh-aFGF has vital clinical value for healing chronic wounds. This consensus provides clinicians with a reference to guide the application not only of rh-aFGF but also of other growth factor drugs with similar mechanisms for CRWs. Full article

(This article belongs to the Special Issue Development of Specific Dosage Form: Wound Dressing, 2nd Edition)

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19 pages, 2901 KB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Novel Furanocoumarin Derivatives: Validation of Anti-Osteoporotic Efficacy In Vitro and In Vivo

by Xiaoming Chen, Shuirong Chen, Qinhan Gao, Gang Li, Yan Geng, Xudong Qian, Hongliang Yao, Qibiao Wu and Jingjing Zhang

Pharmaceuticals 2026, 19(2), 327; https://doi.org/10.3390/ph19020327 - 16 Feb 2026

Viewed by 225

Abstract

Background/Objectives: Osteoporosis is a metabolic bone disease characterized by reduced bone mass and impaired bone microarchitecture. It has become a major clinical challenge due to the limitations of current therapeutic approaches. Isoimperatorin (ISO), a naturally occurring and biologically active furanocoumarin extracted from [...] Read more.

Background/Objectives: Osteoporosis is a metabolic bone disease characterized by reduced bone mass and impaired bone microarchitecture. It has become a major clinical challenge due to the limitations of current therapeutic approaches. Isoimperatorin (ISO), a naturally occurring and biologically active furanocoumarin extracted from various traditional herbals, exhibits therapeutic potential in combating osteoporosis. However, toxicity limits its application. Methods: In vivo, compound B15 was evaluated in an Ovariectomy (OVX) mice model, where treatment was associated with changes in bone microarchitecture parameters, modulation of serum bone metabolism markers, and alterations in the histopathological features of bone tissue. Results: In this study, a new series of furanocoumarin derivatives was designed and synthesized for the treatment of osteoporosis. Compared with ISO, compound B15 has less toxicity and better ability to inhibit osteoclast formation in vitro. Compound B15 could decelerate the progression of osteoporosis in ovariectomized mice. It is worth mentioning that the expression of estradiol in the serum of mice with excised ovaries was significantly increased by compound B15. Conclusions: These results imply that the novel furanocoumarin derivative B15 is a promising therapeutic option for osteoporosis. Full article

(This article belongs to the Section Medicinal Chemistry)

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25 pages, 3323 KB

Open AccessArticle

Design of Experiments in the Formulation and Characterization of 3D-Printed Vaginal Films Loaded with Curcumin Solid Lipid Nanoparticles for Cervical Dysplasia

by Mahek Gulani, Dedeepya Pasupuleti, Yash Harsoda, Snehitha Akkineni, Sarthak Shah, Tanisha Manoj Arte, Emmanuel Adediran, Amarae Ferguson, Nigel D’Souza, Aditi Satoskar, Mohammad Uddin, Lisa Flowers and Martin J. D’Souza

Pharmaceuticals 2026, 19(2), 326; https://doi.org/10.3390/ph19020326 - 16 Feb 2026

Viewed by 388

Abstract

Background/Objectives: Cervical dysplasia, a precursor to cervical cancer, represents a significant global health challenge, particularly in regions like Central America, Africa, and Southeast Asia. Current management approaches rely on surgical or ablative interventions, which can lead to complications, for example, preterm birth [...] Read more.

Background/Objectives: Cervical dysplasia, a precursor to cervical cancer, represents a significant global health challenge, particularly in regions like Central America, Africa, and Southeast Asia. Current management approaches rely on surgical or ablative interventions, which can lead to complications, for example, preterm birth and cervical insufficiency. Therefore, developing non-invasive, localized therapeutic alternatives is of great clinical interest. Curcumin is a natural compound that suppresses the progression of cervical cancer, but it has poor oral bioavailability and high clearance. Methods: We incorporated curcumin into solid lipid nanoparticles, which were then loaded into rapidly dissolving films. These films show the sustained release profile of curcumin at the localized vaginal site, demonstrating release kinetics consistent with the Korsmeyer–Peppas model. Results: The curcumin solid lipid nanoparticles yielded a size of 341 nm and a polydispersity index of 0.373, and the zeta potential was −23.4 mV. The encapsulation efficiency of curcumin solid lipid nanoparticles was 77.27% using a validated HPLC method. FTIR analysis supported successful incorporation of curcumin into the lipid matrix. A Box–Behnken Design of Experiments optimized the key film formulation parameters and yielded a film with a tensile strength of 2.8 mPa, disintegration time of 3 min, folding endurance of 263, film thickness of 0.426 mm and a pH of 4.0. Conclusions: In vitro assays in human cervical carcinoma cells demonstrated enhanced mortality and autophagosome formation by the curcumin solid lipid nanoparticles when compared to free curcumin. Surface expression of MHC I, MHCII, CD40 and CD80 in peripheral dendritic cells was significantly higher in the curcumin solid lipid nanoparticles than in free curcumin. Results show that solid lipid nanoparticles loaded with curcumin effectively stimulate and activate dendritic cells, supporting immune cell activation outside the tumor microenvironment. The proposed pain-free self-administration strategies will lead to increased patient compliance. Full article

(This article belongs to the Section Biopharmaceuticals)

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20 pages, 12409 KB

Open AccessArticle

Fibrinogen-Driven NLRP3 Inflammasome: A Novel Therapeutic Target for Tong-Qiao-Huo-Xue Decoction in Ischemic Stroke

by Yan Wang, Yuqin Peng, Hao Sun, Kai Zhu, Ning Wang and Changzhong Wang

Pharmaceuticals 2026, 19(2), 325; https://doi.org/10.3390/ph19020325 - 15 Feb 2026

Viewed by 343

Abstract

Background: Plasma fibrinogen (FIB) levels exhibit a significant elevation during the acute phase of ischemic stroke (IS), and their dynamic fluctuations serve as important biomarkers for stroke onset, disease progression, and long-term prognosis. Tong-Qiao-Huo-Xue Decoction (TQHXD) is highly effective in treating blood [...] Read more.

Background: Plasma fibrinogen (FIB) levels exhibit a significant elevation during the acute phase of ischemic stroke (IS), and their dynamic fluctuations serve as important biomarkers for stroke onset, disease progression, and long-term prognosis. Tong-Qiao-Huo-Xue Decoction (TQHXD) is highly effective in treating blood stasis syndromes affecting the head and face. Nevertheless, the association between TQHXD and FIB in the underlying mechanism of treating IS warrants further investigation. Methods: Proteomics analysis predicted the potential therapeutic targets of TQHXD for IS. An in vivo model of middle cerebral artery occlusion followed by reperfusion (MCAO/R) was created in mice. To explore the interaction between FIB and NLRP3, as well as to verify the particular healing outcomes of TQHXD. Results: An increased blood–brain barrier (BBB) permeability was observed after MCAO/R, accompanied by substantial accumulation of FIB in the brain. In vivo experiments demonstrated that FIB triggered the activation of the NLRP3 inflammasome in microglia. Proteomic analysis revealed a significant increase in FIB levels following model induction, which were markedly reduced after treatment with TQHXD; KEGG pathway enrichment analysis indicated that these changes were primarily associated with the NOD-like receptor signaling pathway. Laser speckle contrast imaging showed that TQHXD treatment significantly improved cerebral blood flow and attenuated brain injury in mice. Fluorescence imaging, ELISA, and Western blotting results collectively demonstrated that TQHXD effectively reduced FIB accumulation and suppressed NLRP3 inflammasome activation. MD and pull-down experiments further demonstrated a strong interaction strength between FIB and NLRP3. Conclusions: FIB accumulates in the ischemic penumbra following CIRI, while TQHXD can effectively down-regulate FIB expression and inhibit NLRP3 inflammasome activation to mitigate CIRI. These findings provide a novel theoretical foundation and treatment direction for stroke management in clinical settings. Full article

(This article belongs to the Section Pharmacology)

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54 pages, 2004 KB

Open AccessReview

Frontiers in Antibody–Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy

by Xinghan Li, Jiaming Liu, Yitong Meng, Jun Li, Jieling Zhao, Dequan Liu and Xiaodong Zhang

Pharmaceuticals 2026, 19(2), 324; https://doi.org/10.3390/ph19020324 - 15 Feb 2026

Viewed by 483

Abstract

Antibody–drug conjugates (ADCs) represent a transformative class of targeted therapies designed to deliver potent cytotoxic agents specifically to tumor cells, minimizing systemic toxicity. This review provides a comprehensive overview of ADCs, detailing their mechanisms of action, design strategies, and clinical advancements. ADCs utilize [...] Read more.

Antibody–drug conjugates (ADCs) represent a transformative class of targeted therapies designed to deliver potent cytotoxic agents specifically to tumor cells, minimizing systemic toxicity. This review provides a comprehensive overview of ADCs, detailing their mechanisms of action, design strategies, and clinical advancements. ADCs utilize monoclonal antibodies to selectively bind tumor-associated antigens, enabling the precise delivery of toxic payloads to cancer cells. The review explores the critical components of ADCs, including the antibody, linker, and payload, and highlights how these elements can be optimized to improve efficacy and minimize off-target effects. We examine the evolution of ADC design from early constructs to the latest innovations and the development of novel payloads that extend therapeutic possibilities beyond traditional cytotoxic agents. Additionally, we discuss the clinical success of ADCs, with examples from approved therapies such as gemtuzumab ozogamicin, brentuximab vedotin, and trastuzumab emtansine, which have redefined the treatment landscape for various cancers. Despite their success, ADCs face challenges such as tumor heterogeneity, resistance mechanisms, and toxicity, which are actively being addressed through ongoing research. The review concludes with an outlook on the future of ADCs, highlighting emerging strategies in conjugation technology, payload design, and combination therapies that are poised to enhance their therapeutic potential across oncology and other disease areas. Full article

(This article belongs to the Section Biopharmaceuticals)

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19 pages, 1914 KB

Open AccessReview

From Chronic Inflammation to Remodeling: Anthocyanins in the Context of Asthma Management

by Madiha Ajaz, Indu Singh, Lada Vugic, Rati Jani, Ayesha Zahid and Natalie Shilton

Pharmaceuticals 2026, 19(2), 323; https://doi.org/10.3390/ph19020323 - 15 Feb 2026

Viewed by 355

Abstract

Asthma is a prevalent chronic disease posing substantial health and economic challenges globally. Its progression involves key hallmarks such as inflammation and airway remodeling, mediated by multiple inflammatory biomarkers and pathways. Despite the availability of potent therapeutic options, many patients continue to suffer [...] Read more.

Asthma is a prevalent chronic disease posing substantial health and economic challenges globally. Its progression involves key hallmarks such as inflammation and airway remodeling, mediated by multiple inflammatory biomarkers and pathways. Despite the availability of potent therapeutic options, many patients continue to suffer from uncontrolled asthma. The plasminogen activator inhibitor-1 (PAI-1) signaling pathway is critical in asthma exacerbation and remodeling, with elevated PAI-1 levels linked to disease progression. Anthocyanins (ACNs), potent antioxidants and anti-inflammatory compounds, have shown promise in asthma management. Epidemiological studies associate higher ACN intake with a lower risk of asthma and improved lung function. Preclinical models further demonstrate ACNs’ effectiveness in reducing asthma-related inflammatory cytokines, chemokines, and signaling pathways. Additionally, a human trial suggests ACNs can improve symptom control and lung function. While no direct evidence links ACNs to PAI-1 reduction in asthma, studies in other chronic conditions show ACNs reduce PAI-1 levels, supporting their potential role in asthma. This suggests a promising avenue for exploring their effects on airway remodeling. The lack of robust human studies remains a gap. Future research should focus on establishing direct evidence of ACNs’ impact on PAI-1 levels and remodeling in asthma, providing novel insights into managing asthma as an adjunct. Full article

(This article belongs to the Special Issue Plant Extracts with Biological Activity and Potential Antioxidant Action)

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23 pages, 14924 KB

Open AccessArticle

Targeting NPY5R—A Member of the NPY Receptor Family: Pharmacological and Transcriptomic Mechanisms of the Euphorbia Factor L2 Against Lung Adenocarcinoma

by Pengzhuo Tao, Wei Liu, Yongfu Wang, Yajing Xue, Changmin Liu, Yizhen Yuan, Kim Fey Leu, Shilin Chen and Chi Song

Pharmaceuticals 2026, 19(2), 322; https://doi.org/10.3390/ph19020322 - 15 Feb 2026

Viewed by 283

Abstract

Background: Advanced lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths, with existing treatments hampered by drug resistance. This underscores the urgent need to identify novel therapeutic targets. The role of neuropeptide Y (NPY) receptors in LUAD remains unclear, and this [...] Read more.

Background: Advanced lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths, with existing treatments hampered by drug resistance. This underscores the urgent need to identify novel therapeutic targets. The role of neuropeptide Y (NPY) receptors in LUAD remains unclear, and this study aimed to investigate their expression profiles, prognostic significance, and the antitumor potential of Euphorbia Factor L2 (EFL2). Methods: Bioinformatics analyses were performed to evaluate NPY receptors in LUAD. Lentivirus-mediated stable neuropeptide Y receptor 5 (NPY5R) knockdown, functional assays including CCK-8, flow cytometry, and scratch assay, PRESTO-Tango, RNA sequencing (RNA-seq), and qPCR were employed to validate the antitumor effects of EFL2 and the functional role of NPY5R. Results: High expression of NPY5R correlated with poor prognosis and immune cell infiltration in LUAD. EFL2 targeted NPY5R, inhibiting A549 cell proliferation and migration while inducing apoptosis. NPY5R knockdown further enhanced these antitumor effects, and the combination of NPY5R knockdown and EFL2 treatment synergistically enriched extracellular matrix (ECM), phosphatidylinositol 3-kinase (PI3K)-Akt, and mitogen-activated protein kinase (MAPK) pathways. Four potential molecular targets were identified. Conclusions: NPY5R is a promising therapeutic target for LUAD. While no clinical drugs targeting NPY5R are currently available, preclinical evidence supports its potential for anticancer drug development. EFL2 exerts antitumor effects via targeting NPY5R, offering useful guidance for developing novel LUAD therapies. Full article

(This article belongs to the Special Issue Precision Oncology: Targeting Molecular Subtypes in Cancer Therapy)

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32 pages, 1393 KB

Open AccessReview

CopperNostics—Here We Are Now, Entertain Us!

by Santiago Andrés Brühlmann, Martin Walther, Klaus Kopka, Martin Kreller and Oliver C. Kiss

Pharmaceuticals 2026, 19(2), 321; https://doi.org/10.3390/ph19020321 - 15 Feb 2026

Viewed by 845

Abstract

Diagnosis and endoradiotherapy using copper radioisotopes—defined as Theranostics or, more specifically, CopperNostics—have the potential to play a prominent role in modern precision medicine, as demonstrated by the FDA approval of [⁶⁴Cu]Cu-DOTA-TATE (Detectnet). In this review we highlight current developments in [...] Read more.

Diagnosis and endoradiotherapy using copper radioisotopes—defined as Theranostics or, more specifically, CopperNostics—have the potential to play a prominent role in modern precision medicine, as demonstrated by the FDA approval of [⁶⁴Cu]Cu-DOTA-TATE (Detectnet). In this review we highlight current developments in the production, radiochemical purification, quality control, availability, logistics, and regulatory hurdles of the most relevant copper radioisotopes, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu, and ⁶⁷Cu, for nuclear medicine. Radiopharmaceuticals based on their application in registered clinical trials, either as molecular imaging agents, companion diagnostics or therapeutic agents, are also presented addressing unmet medical needs. Full article

(This article belongs to the Collection Will (Radio)Theranostics Hold Up in the 21st Century—and Why?)

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16 pages, 872 KB

Open AccessReview

Next-Generation Biomarkers in Multiple Myeloma: Advancing Diagnosis, Risk Stratification, and Precision Therapy Beyond Current Guidelines

by Marta Marques de Carvalho Lopes, Laura do Amaral Xavier, Silvia Cristina Verde Mendes Nolasco, Simone Rodrigues Ribeiro, Danila Felix Coutinho and Adriano de Paula Sabino

Pharmaceuticals 2026, 19(2), 320; https://doi.org/10.3390/ph19020320 - 14 Feb 2026

Viewed by 449

Abstract

Multiple myeloma (MM) is an oncohematological neoplasm characterized by the abnormal proliferation of neoplastic plasma cells in the bone marrow and the excessive secretion of monoclonal antibodies into the bloodstream. Approximately 3 to 5% of patients present with a variant form of the [...] Read more.

Multiple myeloma (MM) is an oncohematological neoplasm characterized by the abnormal proliferation of neoplastic plasma cells in the bone marrow and the excessive secretion of monoclonal antibodies into the bloodstream. Approximately 3 to 5% of patients present with a variant form of the disease where there is no secretion of monoclonal proteins, characterizing the non-secretory MM picture. It exhibits a highly complex and heterogeneous genetic signature, allowing the disease to be classified into premalignant entities and symptomatic forms. In this context, an integrative narrative review was conducted, encompassing genomic, epigenomic, proteomic, metabolomic, and radiomic biomarkers described in the literature between 2018 and 2025. Emphasis was placed on their translational potential, current limitations in clinical practice, and gaps within recent recommendations. Several categories of biomarkers, particularly ctDNA methylome, single-cell multiomics, proteomics of surface antigens, functional ex vivo assays, and PET/CT radiomics, demonstrate strong potential for enhancing risk stratification, detecting early progression, guiding therapy selection, and identifying novel therapeutic targets. These applications extend beyond existing guideline frameworks. Thus, integrating advanced biomarker platforms can overcome limitations of current diagnostic and therapeutic models and enhance precision strategies across plasma cell disorders. Full article

(This article belongs to the Special Issue Advances in the Treatment of Leukemia, Lymphomas and Plasma Cell Disorders)

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16 pages, 1458 KB

Open AccessArticle

Contributions of Pharmacovigilance to the Understanding of Risks Associated with Ibuprofen: Descriptive and Disproportionality Analysis Using FAERS Data

by Cristina Anamaria Buciuman, Carmen Maximiliana Dobrea, Anca Butuca, Adina Frum, Felicia Gabriela Gligor, Mihai Octavian Botea, Mariana Eugenia Mureșan, Octavia Gligor, Florin Maghiar, Luciana Dobjanschi, Otilia Micle, Claudiu Morgovan and Laura Grațiela Vicaș

Pharmaceuticals 2026, 19(2), 319; https://doi.org/10.3390/ph19020319 - 14 Feb 2026

Viewed by 313

Abstract

Background/Objectives: The objective of this study was to evaluate real-world evidence (Food & Drug Administration database, FAERS) on ibuprofen adverse events (AE) through descriptive and disproportionality analyses. Methods: Signal assessment involved analyzing the top 30 entries with the most reports. The disproportionality analysis [...] Read more.

Background/Objectives: The objective of this study was to evaluate real-world evidence (Food & Drug Administration database, FAERS) on ibuprofen adverse events (AE) through descriptive and disproportionality analyses. Methods: Signal assessment involved analyzing the top 30 entries with the most reports. The disproportionality analysis of signals based on Evans’ criteria (number of reports > 2, chi-square > 4, and PRR > 2) was performed. A total of 70,792 reports submitted to FAERS by the end of 2024 (collected from 97 countries worldwide) indicate ibuprofen as the main suspect. Results: Of these, the highest percentage was attributed to females (n = 33,262, 47.0%) and adult patients (18–65 years) (n = 22,005, 31.1%). In the elderly group (12.4%) and in children and adolescents (11.2%), similar frequencies were reported. Oral administration was the most frequently mentioned route (n = 25,035, 35.4%). A total of 21,077 reports had an unfavorable outcome, of which 3018 (4.3%) reported death. Conclusions: The results highlight potential risks associated with ibuprofen and emphasize the importance of responsible, clinically well-founded administration. The disproportionality analysis can provide valuable information for effectively selecting drug-adverse-effect pairs that warrant further attention. Full article

(This article belongs to the Section Pharmacology)

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60 pages, 1795 KB

Open AccessReview

Diet and Gut Microbiota in Inflammatory Bowel Disease: A Clinical and Nutritional Perspective

by Luisa Bertin, Sonia Facchin, Brigida Barberio, Daria Maniero, Greta Lorenzon, Francesco Cesaroni, Miriana Zanconato, Giulia Romanelli, Francesco Francini-Pesenti, Luca Busetto, Mara Cananzi, Paola Gaio, Luca Bosa, Fabiana Zingone, Laura Gianolio, Oriana M. Damas and Edoardo Vincenzo Savarino

Pharmaceuticals 2026, 19(2), 318; https://doi.org/10.3390/ph19020318 - 14 Feb 2026

Viewed by 841

Abstract

Inflammatory bowel diseases, comprising Crohn’s disease and ulcerative colitis, represent chronic inflammatory disorders with rising global incidence, underscoring the pivotal role of modifiable environmental factors in disease pathogenesis. Diet and intestinal microbiota have emerged as critical bidirectional therapeutic targets through complex interactions with [...] Read more.

Inflammatory bowel diseases, comprising Crohn’s disease and ulcerative colitis, represent chronic inflammatory disorders with rising global incidence, underscoring the pivotal role of modifiable environmental factors in disease pathogenesis. Diet and intestinal microbiota have emerged as critical bidirectional therapeutic targets through complex interactions with host immune responses. Epidemiological evidence demonstrates that healthy and high fiber diets reduce disease risk, while ultra-processed foods and inflammatory dietary patterns increase susceptibility. Therapeutic nutritional interventions, including exclusive enteral nutrition, the Crohn’s Disease Exclusion Diet combined with partial enteral nutrition, and the Mediterranean diet can induce and maintain clinical remission while promoting favorable microbiome modifications characterized by the enrichment of butyrate-producing taxa such as Faecalibacterium prausnitzii and Roseburia species, alongside a reduction in pathogenic Proteobacteria. Micronutrient deficiencies affect up to 78% of patients through malabsorption, chronic blood losses, dietary restrictions, and drug–nutrient interactions. Nutritional status significantly impacts surgical outcomes, with preoperative malnutrition and sarcopenia associated with increased postoperative complications, and it reciprocally influences biologic therapy response. Integration of personalized, microbiome-informed dietary strategies as complementary components of comprehensive treatment plans represents a promising therapeutic frontier, requiring multidisciplinary collaboration, rigorous clinical trials with standardized microbiome analyses, and precision nutrition algorithms accounting for disease phenotype, baseline microbial composition, and individual patient characteristics to optimize outcomes and improve quality of life. Full article

(This article belongs to the Special Issue Research on Diagnosis, Treatment and Related Microbiota in Gastrointestinal Diseases)

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15 pages, 1984 KB

Open AccessArticle

Comparative Evaluation of [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG PET/CT in Metastatic Breast and Lung Cancer: Semiquantitative, Volumetric and Prognostic Assessment

by Sulochana Sarswat, Sanjana Ballal, Madhav Prasad Yadav, Madhavi Tripathi, Prabhat Singh Malik, Sandeep R. Mathur, Frank Rösch and Chandrasekhar Bal

Pharmaceuticals 2026, 19(2), 317; https://doi.org/10.3390/ph19020317 - 14 Feb 2026

Viewed by 234

Abstract

Objective: To compare metastatic lesion detection on [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG PET/CT in metastatic breast and lung cancers and to assess the relationship between PET-derived imaging parameters and progression-free survival (PFS). Methods: In this prospective dual-cohort study, 45 patients (23 breast cancer, 22 lung [...] Read more.

Objective: To compare metastatic lesion detection on [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG PET/CT in metastatic breast and lung cancers and to assess the relationship between PET-derived imaging parameters and progression-free survival (PFS). Methods: In this prospective dual-cohort study, 45 patients (23 breast cancer, 22 lung adenocarcinoma) underwent paired [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG PET/CT within four weeks. Semiquantitative (SUVmax, SUVmean) and volumetric (MTV, TLG, STV, TLF) PET parameters were measured. Metastatic detection was compared, and correlations with PFS were assessed. Results: In breast cancer, [18F]FDG demonstrated higher primary tumor uptake, whereas [68Ga]Ga-DOTA.SA.FAPi showed lower background activity, resulting in higher tumor-to-background ratios for brain and bone metastases. Whole-body volumetric indices (wbTLG, wbTLF) showed strong inverse correlations with PFS. In lung adenocarcinoma, volumetric FAPi-derived parameters (wbTLF, wbSTV) demonstrated modest but significant correlations with PFS. [68Ga]Ga-DOTA.SA.FAPi PET/CT detected more brain metastases than [18F]FDG PET/CT in both cohorts (breast: 15/15 vs. 8/15; lung: 14/14 vs. 4/14). Conclusions: [68Ga]Ga-DOTA.SA.FAPi and [18F]FDG PET/CT provide complementary diagnostic and prognostic information. In metastatic breast cancer, FAPi-derived volumetric parameters strongly correlate with PFS and improve detection of brain metastases. In lung adenocarcinoma, [68Ga]Ga-DOTA.SA.FAPi PET/CT offers low background uptake and prognostically relevant stromal metrics. These findings support a potential role for integrating [68Ga]Ga-DOTA.SA.FAPi PET/CT into disease staging, prognostication, and treatment monitoring. This study did not involve prospective assignment to health-related interventions and therefore did not require clinical trial registration. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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29 pages, 1272 KB

Open AccessReview

Ischemia-Induced Neurodegeneration in Glaucoma: Mechanistic Insights and Translational Opportunities for Psychoplastogen-Based Therapies

by Petra Dolenec, Goran Pelčić, Kristina Pilipović, Jasenka Mršić-Pelčić and Anja Harej Hrkać

Pharmaceuticals 2026, 19(2), 316; https://doi.org/10.3390/ph19020316 - 14 Feb 2026

Viewed by 352

Abstract

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia–reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from [...] Read more.

Glaucoma is increasingly recognized as an ischemic neurodegenerative disorder that extends beyond elevated intraocular pressure (IOP) to involve complex vascular, metabolic, and inflammatory mechanisms. Retinal ganglion cells are particularly vulnerable to ischemia–reperfusion injury, oxidative stress, and chronic neuroinflammation, leading to progressive disconnection from central visual pathways. Current therapies primarily target IOP reduction but fail to address ischemia-driven neurodegeneration or to restore lost neuronal connectivity. Ischemia triggers excitotoxicity, oxidative stress, and a maladaptive inflammatory response involving activated microglia and astrocytes, perpetuating neuronal injury and suppressing intrinsic regenerative capacity. Thus, restoring neural plasticity and mitigating neuroinflammation represent key unmet therapeutic needs. Psychoplastogens are a class of compounds capable of rapidly enhancing structural and functional neuroplasticity and have recently emerged as promising multitarget agents. Compounds such as ketamine, psilocybin, N,N-dimethyltryptamine (DMT), and some newly synthesized non-hallucinogenic analogs act through convergent signaling pathways involving BDNF–TrkB–mTOR, promoting dendritic growth, synaptogenesis, and glial modulation. Beyond their neurotrophic effects, psychoplastogens seem to exert potent immunomodulatory actions. In this review we will explore the interplay between ischemia, neurodegeneration, neuroinflammation, and impaired plasticity in glaucoma, integrating mechanistic insights from cerebral ischemia. We discuss emerging preclinical evidence supporting psychoplastogens as neurorestorative and anti-inflammatory agents, propose their potential application in ocular ischemic neurodegeneration, and outline translational challenges for future studies. Full article

(This article belongs to the Special Issue Novel Drug Compositions for Ischemic Stroke: Mechanisms and Clinical Applications)

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34 pages, 10269 KB

Open AccessArticle

Integrated Computational Investigation of Cannabis sativa Phytoconstituents as Putative Multi-Target Inhibitors in Skin Cancer: A Molecular Docking, Dynamics, and ADMET Profiling Study

by Lamiae El Bouamri, Salma Laaouina, Ibtissam Lakrim, Hassan Nour, Imane Yamari, Abdelouahid Samadi, Mohammed Bouachrine and Samir Chtita

Pharmaceuticals 2026, 19(2), 315; https://doi.org/10.3390/ph19020315 - 13 Feb 2026

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Abstract

Background: Skin cancer progression is driven by the dysregulation of key oncogenic signaling pathways, including EGFR, BRAF V600E, and TGF-β, which collectively promote tumor proliferation, invasion, and metastatic progression. Targeting these pathways using multitarget natural modulators represents a promising therapeutic strategy. Methods [...] Read more.

Background: Skin cancer progression is driven by the dysregulation of key oncogenic signaling pathways, including EGFR, BRAF V600E, and TGF-β, which collectively promote tumor proliferation, invasion, and metastatic progression. Targeting these pathways using multitarget natural modulators represents a promising therapeutic strategy. Methods: In this study, forty-nine phytoconstituents from Cannabis sativa were evaluated using an integrated computational approach to explore their inhibitory potential against EGFR, BRAF V600E, and the TGF-β receptor. Molecular docking was performed to assess binding affinities and interaction profiles, followed by ADMET analysis to evaluate pharmacokinetic and safety properties. The top-ranked compounds were further investigated using 200 ns molecular dynamics simulations and MM-GBSA binding free energy calculations to assess the stability and strength of protein–ligand interactions. Results: Several phytoconstituents exhibited strong binding affinities toward the target proteins, formed stable interactions with key active-site residues, and demonstrated favorable pharmacokinetic profiles with acceptable safety characteristics. Molecular dynamics simulations confirmed the structural stability of the selected protein–ligand complexes, while MM-GBSA analysis supported their favorable binding energetics. Conclusions: These findings suggest that Cannabis sativa phytoconstituents may represent a promising source of multitarget modulators capable of attenuating EGFR, BRAF V600E, and TGF-β driven oncogenic signaling in skin cancer. This study provides a mechanistic framework that supports further in vitro validation and the development of cannabis-derived therapeutic candidates for targeted skin cancer management. Full article

(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery, 2nd Edition)

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21 pages, 5853 KB

Open AccessArticle

Systematic Investigation of Tumor Immune Microenvironment Modulation by Cynomorium songaricum Against Breast Cancer Through Integrated Chemomics, Network Pharmacology and Molecular Docking

by Ze-An Mao, Mei-Ling Zhang, Zi-Yi An and Wei-Lin Jin

Pharmaceuticals 2026, 19(2), 314; https://doi.org/10.3390/ph19020314 - 13 Feb 2026

Viewed by 252

Abstract

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality in women, with therapeutic resistance frequently arising from tumor heterogeneity and an immunosuppressive tumor immune microenvironment (TIME). While Cynomorium songaricum Rupr. (CS) has been used traditionally in Chinese medicine and exhibits preliminary [...] Read more.

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality in women, with therapeutic resistance frequently arising from tumor heterogeneity and an immunosuppressive tumor immune microenvironment (TIME). While Cynomorium songaricum Rupr. (CS) has been used traditionally in Chinese medicine and exhibits preliminary anti-tumor activity, its bioactive constituents and precise mechanisms against breast cancer remain to be elucidated. Methods: The chemical constituents of CS were systematically profiled using ultra-high-performance liquid chromatography coupled with Q Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap MS/MS). Network pharmacology and functional enrichment analyses were performed to identify immuno-related targets and pathways, followed by molecular docking to prioritize component–target pairs. Molecular dynamics (MD) simulations were conducted to validate the stability of a representative docked complex and to characterize binding stability, interaction persistence, molecular mechanics/(Poisson–Boltzmann) surface area (MM/(P)BSA) energetics, and principal component analysis (PCA)-based conformational landscapes. Results: We identified 1100 compounds, of which 84 satisfied the in silico drug-likeness criteria, including 12 phenylpropanoids, 4 terpenes, 35 flavonoids, 2 quinones, 1 phenol, 3 alkaloids, and other phytochemicals. Network pharmacology analysis revealed 776 overlapping targets associated with both breast cancer and immune regulation. Functional enrichment analysis underscored significant involvement in immune-related pathways, and molecular docking studies supported high-affinity interactions between the components and their targets. MD analyses further supported a stable bound ensemble for the representative SRC–Tomentogenin complex during the equilibrated window, with persistent pocket occupancy, consistent interaction signatures, favorable MM/(P)BSA binding energetics, and a concentrated low-energy basin on the PCA-based free energy landscape. Conclusions: These findings elucidate the chemical basis of CS and uncover its immunomodulatory mechanism against breast cancer, offering a foundation for developing CS-based immunotherapeutic strategies and supporting multi-target drug discovery from traditional medicines. Full article

(This article belongs to the Special Issue Medicinal Plants: Exploring Plant-Based Bioactive Compounds for Cancer and Metabolic Diseases Prevention and Intervention)

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Pharmaceuticals, Volume 19, Issue 2 (February 2026) – 151 articles

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