Beneficial Synergistic Roles of Flavonoids and Vitamin C Against Inflammatory Complications, Cancer, and Cardiovascular Diseases: A Comprehensive Review

Abstract

Flavonoids and vitamin C are two of the most extensively studied dietary bioactive compounds, with growing evidence supporting their roles in the modulation of oxidative stress, inflammation, thrombosis, and cancer progression. Flavonoids, a diverse subclass of polyphenols, exhibit promising antioxidant, anti-inflammatory, and anticancer properties. However, their clinical translation is frequently hindered by poor solubility, limited stability, and low bioavailability. Vitamin C (ascorbic acid), a well-known established antioxidant that can also exert pro-oxidant effects at pharmacological concentrations, demonstrates anti-inflammatory, antithrombotic, immune-modulatory, and endothelial-protective activities across various experimental and clinical disease models. Recent studies have highlighted a promising synergistic interaction between flavonoids and vitamin C, wherein flavonoids enhance the stability, recycling, and intestinal absorption of vitamin C, while vitamin C augments the antioxidant capacity and cellular bioactivity of flavonoids. This review critically summarizes current evidence regarding the independent and combined effects of flavonoids and vitamin C, with particular emphasis on their roles in cancer, cardiovascular diseases, and inflammation-related complications. Key molecular mechanisms, including redox signaling modulation, inhibition of pro-inflammatory pathways, and regulation of thrombosis- and angiogenesis-related processes, are discussed. Furthermore, therapeutic opportunities, limitations, and challenges related to bioavailability, dosing strategies, and clinical translation are addressed. Understanding the synergistic actions of flavonoids and vitamin C may provide valuable insights for the development of novel nutraceutical formulations or adjuvant therapeutic approaches in chronic and inflammation-driven diseases.

1. Introduction

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for nearly 18 million deaths annually, according to the World Health Organization [1]. These disorders—including coronary artery disease, heart failure, and stroke—are closely associated with chronic inflammation, thrombosis, and platelet activation. Beyond CVDs, these same pathophysiological processes also contribute to cancer initiation, malignancy, progression, and metastasis. While inflammation and thrombosis initially serve as protective host-defense mechanisms, their prolonged or dysregulated activation can shift toward pathological drivers of chronic disease [2].

Interestingly, inflammation and thrombosis are rapidly triggered in response to cellular injury or pathogenic insults. However, when tissue damage is unresolved, persistent inflammatory signaling and sustained thrombotic activity may promote disease onset and progression. In chronic inflammatory states, prolonged platelet hyperactivation plays a critical role by amplifying inflammatory cascades, promoting endothelial dysfunction, and facilitating thrombus formation, thereby linking ascending inflammation, thrombosis, and malignant cancer-related processes [2,3,4,5].

Platelets, traditionally viewed as mediators of hemostasis, are now recognized as central regulators of inflammation, immune responses, and tumor biology [6]. Activated platelets interact with immune, endothelial, and circulating tumor cells, contributing to vascular inflammation, atherogenesis, and tumor growth and dissemination. Hence, therapeutic strategies focus on modulating platelet activation and inflammation-related signaling pathways. In this context, bioactive compounds of natural origin have attracted significant interest as a promising preventive or adjunctive therapeutic agents [7,8].

Among these, phenolic compounds and particularly flavonoids, a major subclass of polyphenols abundantly present in fruits, vegetables, and plant-derived products, have emerged as promising candidates [9]. Flavonoids exhibit well-documented antioxidant, anti-inflammatory, and anticancer activities, partly mediated through the modulation of platelet activation, redox-sensitive signaling pathways, and inflammatory mediators. Their natural origin and broad biological activity profile have contributed to growing scientific and clinical interest [9,10,11,12]. However, despite encouraging preclinical evidence, the clinical application of flavonoids remains limited due to poor solubility, metabolic instability, and low bioavailability. As a result, synergistic strategies involving complementary bioactive compounds have been proposed to enhance their therapeutic efficacy [13,14].

Vitamin C (ascorbic acid) is another widely studied dietary bioactive compound with established biological relevance. It is an essential water-soluble micronutrient organic compound belonging to the group of unsaturated polyhydroxy alcohols and is abundantly found in fruits such as oranges and mandarins [15]. Beyond its classical redox abilities and antioxidant function, vitamin C exerts strong anti-inflammatory, antithrombotic, immune-modulatory, and anticancer effects, and at pharmacological concentrations, it may also display pro-oxidant activity, selectively in cancer cells [16]. Recent studies have increasingly explored the possible synergistic interactions between vitamin C and flavonoids, demonstrating improvements in flavonoid stability, redox recycling, intestinal absorption, and overall biological activity and therapeutic potential against CVDs, cancer progression, and related inflammatory and oxidative stress cascades [16,17,18].

While the term “synergy” is frequently employed to describe the combined benefits of flavonoids and vitamin C, it is essential to distinguish between the additive effects, where the total outcome is simply the sum of individual contributions, and true pharmacological synergy, where the interaction of these compounds produces a potentiation that significantly exceeds the predicted sum of their independent activities [16,17,18].

The novelty of the present review lies in its integrated, mechanistically focused analysis of flavonoid–vitamin C combinations across inflammatory, cardiovascular, and cancer-related contexts, rather than treating these compounds or disease states in isolation. Unlike prior reviews that primarily emphasize descriptive compound-by-compound effects or single-disease outcomes, this work systematically examines the shared molecular pathways—including redox signaling, platelet activation, inflammatory mediator regulation, thrombosis, angiogenesis, and immune modulation—through which flavonoids and vitamin C may converge to influence disease progression. Particular emphasis is placed on distinguishing experimentally validated synergistic interactions from additive or putative effects, critically evaluating pharmacokinetic and dosing limitations, and differentiating preclinical findings from clinically relevant evidence. The key highlights of this comprehensive review are illustrated in Figure 1.

2. Search Strategy

A structured literature search was conducted in PubMed, Scopus, and Web of Science, with supplementary screening in Google Scholar, to identify studies examining vitamin C, flavonoids, and their hidden synergistic effects in cancer, cardiovascular diseases (CVDs), and thrombo-inflammatory conditions. The search covered publications from January 2000 to September 2025 and was restricted to peer-reviewed articles published in English.

Search terms were combined using Boolean operators and organized into three main categories:

(i)

bioactive compounds (vitamin C, flavonoids, including quercetin and catechin);

(ii)

biological processes and disease outcomes (cancer, cardiovascular disease, inflammation, platelet activation, thrombosis, oxidative stress); and

(iii)

therapeutic context (synergy, antioxidant activity, nutraceuticals, adjuvant therapy).

Representative search strings included “vitamin C AND flavonoids AND cancer”, “vitamin C AND platelet activation”, and “flavonoids AND cardiovascular disease”.

Studies were initially screened based on titles and abstracts, followed by full-text evaluation. Articles focusing exclusively on unrelated phytochemicals, non-dietary antioxidants, or lacking mechanistic or disease-relevant data were excluded. Review articles were used primarily to identify additional primary studies and contextualize findings but were not treated as primary evidence unless explicitly stated.

To support thematic organization and assess keyword relevance, a bibliometric analysis was performed using VOSviewer (version 1.6.20). Keyword co-occurrence mapping facilitated the identification of major research clusters related to cancer biology, cardiovascular disease, inflammation, oxidative stress, platelet activation, and synergistic therapeutic strategies, thereby guiding the structured synthesis of the reviewed literature (Figure 2).

3. Flavonoids: Diversity, Mechanisms, and Health Benefits

3.1. Flavonoids and Their Health-Promoting Effects

Flavonoids, also referred to as bioflavonoids, are a widely distributed class of polyphenols, predominantly found in plant-based foods. Major dietary sources include fruits, vegetables, grains, herbs, and beverages such as tea, wine, and fruit juices, where flavonoids contribute to pigmentation, flavor, or pharmacological activities [9,19,20]. Historically, the medicinal use of flavonoid-rich natural products dates back to Ancient Greece, where Hippocrates reported the therapeutic application of propolis for the treatment of sores and ulcers, highlighting early recognition of their healing properties [21].

Structurally, flavonoids are characterized by a 15 (C₆-C₃-C₃)-carbon skeleton composed of two aromatic benzene rings (A and B) linked by a heterocyclic oxygen-containing pyran ring (C). This is formally referred to as the 2-phenylchromane skeleton. Based on variations in the oxidation state and substitution patterns, flavonoids are classified into several subclasses, including flavones, flavonols, flavan-3-ols, flavanones, isoflavones, anthocyanins, and anthocyanidins [9,10].

Flavones reveal a double bond between C₂-C₃ and a ketone at C₄ (e.g., apigenin), flavonols have a similar structure to that of flavones plus a hydroxyl group at C₃ (e.g., quercetin, kaempferol), while flavanones share a saturated C₂-C₃ bond (e.g., naringenin). Moreover, flavanols (catechins) do not reveal a C₄ carbonyl, but a saturated C ring, whereas isoflavones structurally own a B ring attached at C₃ rather than C₂. Finally, anthocyanidins are aglycone (non-sugar forms) based on a positively charged flavylium cation, being chemically less stable (e.g., cyanidin), while anthocyanins are the glycosylated derivatives of anthocyanidins, owning one or more sugar moieties (e.g., glucose) attached usually at C₃, thus being more stable and water soluble (e.g., cyanidin 3-O-glucoside) [9,10].

In natural sources, flavonoids occur either as aglycones or conjugated forms, such as glycosides, tannins, or proanthocyanidins. Owing to their diverse chemical structures, flavonoids exhibit several biological activities, including antioxidant, anti-inflammatory, antithrombotic, cardioprotective, and anticancer effects [9,10,11,12]. The predominant flavonoids, according to Tsoupras et al. [22], are presented in Figure 3, whereas a thorough structural overview of all flavonoid classes is presented in Figure 4.

At the molecular level, flavonoids interact with multiple signaling pathways involved in oxidative stress regulation, inflammation, apoptosis, angiogenesis, and immune responses. Accumulating evidence indicates that flavonoids modulate key regulators of carcinogenesis and tumor progression and are implicated in several cancer types, including leukemia and breast cancer [17,23,24]. Specifically, flavonoids have been shown to inhibit tumor growth, suppress metastasis, and promote apoptosis, thereby targeting critical stages of cancer development [9]. Compounds such as fisetin and quercetin have been shown to modulate oncogenic signaling and induce programmed cell death. In addition, flavonoids interact with reactive oxygen species (ROS), thus influencing redox homeostasis, a central process in both tumor initiation and progression [5,11,13].

Despite their promising biological activity, flavonoids face important limitations related to poor aqueous solubility, limited intestinal absorption, extensive first-pass metabolism, and systemic bioavailability. These constraints notably hinder their clinical translation [12,25]. Consequently, current research focuses on synergistic strategies, including combination with other bioactive compounds, formulation, and co-administration approaches, to enhance flavonoid bioavailability and therapeutic efficacy. Furthermore, the efficacy of flavonoids is influenced by several factors, including dose, chemical structure, food matrix, co-administration with other compounds or drugs, and individual health status, highlighting the need for further mechanistic and clinical investigation [26].

Natural bioactives are characterized by several secondary metabolites that offer multitargeted therapeutic benefits. As illustrated in Figure 5, the classification of polyphenols into distinct groups, such as flavonols, curcuminoids, and flavones, reveals a precise correlation between molecular structure and biological efficacy. For instance, while compounds like quercetin and curcumin are highlighted for their robust anti-inflammatory and antioxidant capabilities [12,27,28,29], the flavan-3-ols, specifically catechin and epigallocatechin gallate (EGCG) [30,31], demonstrate a specialized role in gene regulation and the mitigation of CVD risk. This mapping emphasized the transition from natural botanical knowledge to a rigorous, evidence-based understanding of how these molecules interact with human physiology. By isolating these ingredients, the modern cosmetics and nutraceutical industries can move beyond crude extracts toward reproducible formulations that support systemic health and cellular longevity.

A summary of representative flavonoids and flavonoid-based combinations, their bioactive subclasses, and associated health-promoting effects across inflammatory, cardiovascular, and cancer-related contexts which will be further analyzed in the subsections below, is thoroughly provided in

Table 1. Summary of Representative Flavonoid Bioactives and Their Health Benefits.

Flavonoid or Bioactive Combination	Bioactive Subclass	Health-Promoting Benefits	References
Quercetin	Flavonol	Improved PCOS parameters and reduced TNF-α and LH Decreased plasma resistin, weight loss, improved fasting insulin levels, and lowered insulin resistance in overweight or obese PCOS women Reduced IHD mortality Decreased tumor volume Lower oxidative stress markers like iron, MDA, and ROS levels, and increased GSH, GPX4, and SLC7A11 concentrations	[11,27,28,32,33,34,35,36]
Isoquercetin	Flavonol	PDI activity inhibition and thrombin reduction	[34]
Catechin	Flavan-3-ol	Apoptosis promotion in leukemia, DNA methyltransferase inhibition, and PODXL gene modulation	[30,37]
Epigallocatechin gallate (EGCG)	Flavan-3-ol	Apoptosis induction, cell proliferation inhibition, and PI3K/Akt regulation Decreased oxidative stress and inflammatory markers like TNF-α, IL-6, and ROS, while increasing Sirt1 and FOXO1 Improved lipid profiles, lower CVD risk, and promoted anti-inflammatory effects Modulated sex steroid hormone, increased estradiol, and decreased estrone and androstenedione levels Lowered API and ADI in advanced lung cancer Reduced metabolic kisspeptin, triglyceride, and blood pressure Modulated lipid metabolism without impacting adiponectin or UCP1 levels	[31,38,39,40,41,42,43,44,45]
Curcumin	Curcuminoid	Antioxidant and anticancer properties Inhibited EMT genes and suppressed Rho-A signaling in breast cancer cells Modulated specific microRNA cascades for targeted gene therapy Reduced oral mucositis, inflammation, and pain Significant reduction in PSA progression and IAD, without adverse effects in prostate cancer patients Revealed radiosensitizing effects in cervical cancer, reduced cachexia progression in patients with solid tumors, and enhanced metabolism in PCOS women Decreased body fat mass, fat percentage, and basal metabolic rate, and increased hand grip muscle strength Lowered FPG and dehydroepiandrosterone levels and elevated estradiol	[12,46,47,48,49,50,51,52]
Apigenin	Flavone	Tumor angiogenesis inhibition, breast cancer prevention, and p53 expression Inhibited TXA2 signaling, promoted anoikis, and modulated GTPase signaling Suppressed cell invasion, migration, proliferation, and lipid metabolism by suppressing KDM1A expression	[53,54,55]
Wogonin	Flavone	Anticancer and apoptosis induction Modulated fatty acid oxidation and synthesis, and increased ROS accumulation Reduced PANC-1 and AsPC-1 cell viability by increased iron levels, lipid peroxidation, and ROS accumulation Suppressed GSH levels and the expression of Nrf2, GPX4, and SLC7A11 Inhibited cell proliferation, invasion, and migration, while inducing apoptosis and lowering cancer protein expression	[56,57,58,59]
Hispidulin	Flavone	Anticancer, apoptosis induction, and tumor growth inhibition Reduced colony formation, inhibited cell proliferation, and induced apoptosis Regulated Akt signaling and Bcl-2/Bax ratio, leading to impaired cell migration, invasion, and survival Decreased ERK phosphorylation, inhibiting A2058 cell migration and proliferation Enhanced ROS generation, suppressed Ki-67 expression, and increased activation of caspase-3 and phosphorylated eIF2α Hispidulin combined with TGF-β1 exerted growth-suppressive effects in breast cancer cells, reduced vimentin expression, and increased E-cadherin levels	[60,61,62,63,64]
Pectolinarigenin	Flavone	Downregulated RRM2, induced G2/M cell cycle arrest, and enhanced autophagy via proteasomal and autolysosomal degradation cascades in GBM melanoma Inhibited tumor metastasis by suppressing STAT3 signaling and increasing CD8+ T-cell-mediated immune responses Induced apoptosis and inhibited cell proliferation via mitochondrial-related apoptosis Regulated OPA1 acetylation and SIRT3 activity Inhibited cell viability, proliferation, and migration Downregulated MMP-2 and MMP-9 and induced alterations in TIMP2 and STAT3 expression Modulated tumor progression via MAPK/mTOR/Akt/PI3K signaling with promising prospects in cancer therapy	[65,66,67,68]
Anthocyanin + Curcumin	Combination	Anti-inflammatory effect and improved metabolic markers Increased IL-6 and suppressed adiponectin levels, both of which exhibited an inverse relationship with dysplasia grade Improvement in the metabolic function of adenomatous polyps	[69]
Curcumin + Piperine	Combination	Anticancer effects in leukemia, cell proliferation inhibition, apoptosis induction, and suppression of anti-apoptotic proteins	[70]
Epicatechin + Quercetin	Combination	Enhanced antioxidant activity (DPPH assay) Reduced LDL cholesterol, total cholesterol, triglycerides, and fasting plasma glucose	[71]
EGCG + Quercetin	Combination	Increased plasma concentrations of quercetin and its metabolite isorhamnetin compared with ECGC or placebo EGCG significantly enhanced quercetin bioavailability and polyphenol metabolism	[72]
EGCG + Sulforaphane	Combination	Reduced estrogen receptor-negative mammary tumors, modulated gut microbiota composition, induced apoptosis, and synergistically inhibited breast cancer cell growth	[73]
Luteolin + Quercetin	Combination	Apoptosis synergy, cancer pathways modulation, and anticancer effect enhancement Modulated PI3K/Akt signaling, a key regulator of carcinogenesis, and induced apoptosis in nearly 50% of treated cells, while also inhibiting cancer cell migration	[74]
Apigenin + Vorinostat	Combination	Exhibited synergistic pro-apoptotic effects in TNBC cells, enhanced cell cycle arrest, and suppressed tumor cell proliferation and metastasis	[75]
Luteolin + Curcumin	Combination	Suppressed and regulated TNBC, leading to tumor size reduction Decreased tumor xenograft growth and volume in breast cancer models, reduced tumor size, and downregulated MYC expression Increased STAT1 and OAS1 activity and suppressed TNBC progression through modulating the SMAD/TGF-β pathway	[76]
Luteolin + Xanthohumol	Combination	Modulated gut microbiota and prevented colorectal cancer Demonstrated potent antitumor and anti-inflammatory effects in chemically induced colorectal cancer mouse models	[77]
Nobiletin + DHA	Combination	Enhanced ERK phosphorylation, p38, and nuclear translocation of NF-κΒ and produced synergistic anti-inflammatory effects	[78]
Luteolin + Tangeretin	Combination	Suppressed LPS-stimulated inflammatory responses in RA 264.7 macrophages, leading to reduced COX-2 and mRNA expression Inhibited pro-inflammatory mediators like PGE2 compared with individual treatments, and lowered IL-1β and IL-6 levels	[79]

.

3.1.1. Flavonols

Quercetin is one of the most extensively studied flavonols and a predominant bioactive compound in plant-derived foods, including apples, onions, and berries [11]. It has demonstrated broad therapeutic benefits across multiple biological processes, particularly in inflammation, metabolic disorders, CVDs, and cancer [27].

Clinical studies investigating quercetin supplementation in patients with polycystic ovary syndrome (PCOS) reported significant reductions in luteinizing hormone (LH) and tumor necrosis factor-α (TNF-α) levels, accompanied by improvements in oocyte quality, embryo grading, and pregnancy rates [32]. Additional benefits included reductions in plasma resistin levels, weight loss, improvements in fasting insulin levels, and decreased insulin resistance in overweight or obese women with PCOS [28].

Epidemiological evidence has linked dietary quercetin intake with reduced mortality from ischemic heart disease (IHD), particularly when derived from onion consumption, although such associations were not consistently observed with quercetin intake from tea [33]. Furthermore, isoquercetin, a glycosylated derivative of quercetin, has revealed inhibitory effects on protein disulfide isomerase (PDI), leading to reduced thrombin generation and highlighting its potential in coagulation-associated conditions [34].

In vivo studies using breast cancer mouse models (BCRDs) revealed that quercetin administration significantly inhibited carcinogenesis and tumor volume while promoting apoptosis and necrosis [35], by modulating oxidative stress pathways [36]. Collectively, these findings underscore quercetin’s multifaceted biological activity and potential relevance in disease prevention and therapy.

3.1.2. Flavan-3-ols (Flavans)

Catechins, particularly those derived from green tea exhibit notable anticancer properties, including apoptosis induction, oncogenic signaling modulation, and tumor growth inhibition [30]. In acute lymphoblastic leukemia models, catechins suppressed leukemic cell proliferation through inhibition of DNA methyltransferases and regulation of micro-RNA associated pathways, leading to increased apoptosis [37].

Epigallocatechin gallate (EGCG), one of the most bioactive catechin derivatives and has demonstrated anticancer, anti-inflammatory, and cardiometabolic effects. EGCG induces apoptosis, inhibits cell proliferation, and modulates key oncogenic pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling [38]. In vivo studies in high-fat diet-induced obese rats demonstrated that EGCG decreased oxidative stress and inflammatory markers, while increasing proteins associated with longevity and metabolic regulation and metabolic profiles and cardiovascular risk markers [31]. In post-menopausal women at high risk of breast cancer, EGCG supplementation modulated sex steroid hormone levels, [39], linked to elevated breast cancer risk [40].

Phase I/II clinical trials confirmed the safety of ECGC at non-toxic doses, with additional benefits such as imaging enhancement, lower pneumonia incidence, and decreased intensive care unit (ICU) admissions [41]. Likewise, an in vivo study regarding EGCG consumption exhibited lower radiation therapy oncology group (RTOG) scores and numerical rating scale (NRS) levels in patients, along with acute radiation-induced esophagitis (ARIE) severity suppression, without any reported allergenicity or dose-limiting toxicity [42]. EGCG consumption also revealed lower acute pain (APIs) and acute dysphagia indexes (ADIs), showcasing its promising beneficial activity against advanced lung cancer [43]. EGCG was also found to be safe and well-tolerated in reproductive applications, including intrauterine insemination with ovarian stimulation, without any reported side effects [44]. Additionally, EGCG has promoted beneficial effects on metabolic risk factors, including lipid regulation and blood pressure reduction [45].

3.1.3. Polyphenols/Curcuminoids

Curcumin, the principal curcuminoid derived from turmeric, has generated considerable attention for its anti-inflammatory, antioxidant, and anticancer properties [47], although its clinical application is limited by poor bioavailability [12].

Experimental studies have demonstrated that curcumin inhibits epithelial–mesenchymal transition (EMT)-related genes and suppresses Rho-A signaling in breast cancer cells, thereby reducing cell migration, through microRNA mechanisms involving miR-34a [46]. Clinical trials in patients with head and neck cancer undergoing radiotherapy reported that curcumin in the form of soft gels, mouthwash, or placebo, both orally and topically, reduced oral mucositis, inflammation, and pain, while improving oral mucosal healing [48].

Interestingly, oral curcumin intake revealed a significant reduction in PSA progression in patients with prostate cancer and intermittent androgen deprivation (IAD), without any recorded adverse effects or abnormalities in the health-related quality of life (HRQL) levels [49]. Moreover, curcumin also demonstrated radiosensitizing effects in cervical cancer, reduced cachexia progression in patients with solid tumors, and provided metabolic benefits in women with PCOS. More specifically, protein levels were 75% lower in the curcumin group, while 85% of the curcumin-treated patients achieved a complete radiotherapy response [50]. Curcumin treatment in cancer cachexia among patients with solid tumors resulted in a decrease in body fat mass, fat percentage, and basal metabolic rate, along with hand grip muscle strength effects and a slower progression of coronary artery calcium scores (CACS) [51]. Plus, curcumin was proven beneficial for PCOS-suffering women, as confirmed by the reductions in fasting plasma glucose (FPG) and dehydroepiandrosterone levels, along with a notable increase in estradiol [52].

3.1.4. Flavones

Apigenin, a flavone abundant in celery, exhibits notable anticancer and anti-angiogenic properties. In breast cancer models, it inhibited thromboxane A₂ (T_XA₂) signaling and activated p53 expression, promoting anoikis and tumor suppression [53]. Both in vitro and in vivo studies support its ability to inhibit angiogenesis and modulate guanosine triphosphatase GTPase-related signaling cascades [55]. In hepatocellular carcinoma (HCC), apigenin suppressed cell invasion, migration, proliferation, and lipid metabolism by suppressing klysine demethylase 1A KDM1A expression [54].

Wogonin has also been extensively investigated for its antitumor activity across multiple cancer models. In prostate cancer, in vitro and in vivo studies displayed that wogonin induced apoptosis involving a mitochondrial–mediated apoptotic pathway, along with the modulation of fatty acid oxidation and synthesis [56]. In pancreatic cancer models, wogonin treatment reduced viability by increasing iron levels, lipid peroxidation, the expression of redox-regulating proteins [57]. Additional studies in colorectal cancer models reported that wogonin inhibited cell proliferation, invasion, and migration, while inducing apoptosis and reducing the expression of cancer-associated proteins, ultimately leading to tumor growth suppression and cancer metastasis prevention [58]. However, wogonin pretreatment increased radioresistance in breast cancer cells indicating that further investigation is needed to rule out potential complications in radiotherapeutic regimens [59].

Hispidulin has emerged as another promising flavone with notable anticancer activity. In nasopharyngeal carcinoma (CNE-2Z) cells, hispidulin significantly reduced colony formation, inhibited cell proliferation, and induced apoptosis [60]. These effects were associated with regulation of Akt signaling and the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio, leading to impaired cell migration, invasion, and survival, and were further validated in vivo [60]. In prostate cancer models, hispidulin treatment promoted autophagy, necrosis, and apoptosis, resulting in suppressed tumorigenesis [61]. Moreover, hispidulin demonstrated anticancer activity in melanoma cells by reducing Akt and extracellular signal-regulated kinase (ERK) phosphorylation, thereby inhibiting A2058 cell migration and proliferation, while effectively inducing apoptosis [62].

In non-small cell lung cancer (NSCLC) models, both in vitro and in vivo studies showed that hispidulin inhibited colony formation in a dose–dependent manner [63]. This effect was accompanied by enhanced ROS generation, induction of apoptosis via endoplasmic reticulum stress pathways, suppression of Ki-67 expression, and increased activation of caspase-3 and phosphorylated eIF2α, collectively contributing to tumor growth inhibition [63]. Furthermore, hispidulin in combination with transforming growth factor-β1 (TGF-β1) exerted growth-suppressive effects in breast cancer cells by reducing vimentin expression and increasing E-cadherin levels, indicating hispidulin’s efficacy towards the inhibition of EMT and downregulation of cell migration [64].

Pectolinarigenin (PECT) has demonstrated encouraging antitumor activity in several cancer models. In glioblastoma (GBM), PECT targeted and downregulated ribonucleotide reductase M2 (RRM2), resulting in G2/M cell cycle arrest and enhanced autophagy via proteasomal and autolysosomal degradation cascades, highlighting its therapeutic benefits in GBM treatment [65]. In breast cancer cells, MTT assays revealed that PECT inhibited tumor metastasis by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway and increasing CD8⁺ T-cell-mediated immune responses via mitochondrial-related apoptotic pathways and modulation of cancer-associated protein expression [66].

In melanoma models, PECT inhibited cell viability, proliferation, and migration while promoting apoptosis [67]. In these models, PECT also downregulated matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and induced alterations in tissue inhibitor of metalloproteinases 2 (TIMP2) and STAT3 expression [68]. Collectively, these findings indicate that pectolinarigenin modulates tumor progression via the mitogen-activated protein kinase (MAPK)/mammalian target of rapamycin (mTOR)/Akt/PI3K signaling, underscoring its promising prospects in cancer therapy [68].

3.2. Combination of Flavonoids with Other Bioactive Compounds

Increasing evidence indicates that flavonoids exhibit enhanced biological activity when administered in combination, often demonstrating synergistic effects that surpass those of individual compounds. Clinical studies in patients with adenomatous polyps revealed that combined anthocyanin and curcumin supplementation improved metabolic and inflammatory biomarkers. Specifically, this combination increased IL-6 and suppressed adiponectin levels, both of which exhibited an inverse relationship with dysplasia grade after treatment, suggesting a possible improvement in metabolic function related to adenomatous polyps [69]. Similarly, curcumin and piperine synergy significantly inhibited leukemia cell proliferation and promoted apoptosis [70].

The antioxidant effects of flavonoid combinations has also been explored in functional food formulations. In a study evaluating bread enriched with epicatechin and quercetin, enhanced antioxidant activity was observed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In addition, consumption of the flavonoid-enriched bread resulted in significant reductions in low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and fasting plasma glucose compared with control bread, indicating improved biochemical and metabolic profiles [71].

Synergistic interactions between quercetin and EGCG have been explored in prostate tissue, blood, and urine samples. Combined administration increased plasma concentrations of quercetin and its metabolite isorhamnetin compared with ECGC or placebo alone, underscoring EGCG’s ability to enhance quercetin bioavailability and polyphenol metabolism [72]. In another study, sulforaphane (SFN)-rich broccoli sprouts and EGCG were examined in transgenic mouse models. This combination led to a reduction in estrogen receptor-negative mammary tumors, modulation of gut microbiota composition, induction of apoptosis, and synergistic inhibition of breast cancer cell growth [73].

Combinations of structurally related flavonoids have also demonstrated synergistic anticancer effects. Quercetin combined with luteolin modulated the PI3K/Akt signaling pathway, a key regulator of carcinogenesis, and induced apoptosis in nearly 50% of treated cells, while also inhibiting cancer cell migration [74]. These findings support the flavonoid combinations’ possible benefits in cancer prevention and therapy [74]. Moreover, the combination of apigenin with the histone deacetylase inhibitor vorinostat exhibited synergistic pro-apoptotic effects in triple-negative breast cancer (TNBC) cells, enhancing cell cycle arrest and suppressing tumor cell proliferation and metastasis [75].

Broader combinational approaches have also been evaluated. A study investigating the anticancer potential of a mixture of 12 flavonoids reported that the combination of luteolin with curcumin decreased tumor xenograft growth and volume in breast cancer models [76]. Combinations of luteolin or curcumin reduced tumor size and downregulated MYC expression and other TNBC-associated factors. These effects were linked to increased STAT1 and 2′,-5′-oligoadenylate synthetase 1 (OAS1) activity and suppression of TNBC progression through modulation of the SMAD/TGF-β pathway [76]. Plus, luteolin combined with xanthohumol demonstrated propitious antitumor and anti-inflammatory effects in chemically induced colorectal cancer mouse models, accompanied by favorable modulation of the gut microbiota [77].

Recently, a combination of nobiletin, primarily sourced from citrus peels, with docosahexaenoic acid (DHA) produced synergistic anti-inflammatory effects in macrophage models, demonstrating enhanced ERK phosphorylation and p38 and nuclear translocation of the nuclear factor κΒ (NF-κΒ) [78]. Similarly, luteolin and tangeretin synergistically suppressed lipopolysaccharide (LPS)-stimulated inflammatory responses in RA 264.7 macrophages, leading to reduced cyclooxygenase-2 (COX-2) protein and mRNA expression, stronger inhibition of pro-inflammatory mediators like prostaglandin E₂ (PGE₂) compared with individual treatments, and lower levels of IL-1β and IL-6 [79].

Collectively, these findings support the potential of bioflavonoids as adjunctive agents capable of enhancing therapeutic efficacy, overcoming drug resistance, and reducing treatment-related toxicity. However, careful evaluation of pharmacokinetic interactions, optimal dosing, and clinical safety is essential before their routine incorporation into standard therapeutic regimens.

3.3. Potential Benefits of Bioflavonoids Combined with Conventional Therapies

Growing evidence indicates that bioflavonoids may act as adjuvant agents in conventional therapies, enhancing therapeutic efficacy, modulating drug resistance, or mitigating treatment-related adverse effects. However, their interaction with pharmaceutical agents may be either beneficial or detrimental, depending on the compound, dose, and metabolic pathways involved. In this context, a clinical study investigating ECGC, a major green tea catechin, and nintedanib in patients with fibrotic interstitial lung disease (ILD) demonstrated a clinically relevant drug-nutrient interaction. Co-administration resulted in reduced systemic exposure to nintedanib due to induction of the ABCB1 efflux transporter, indicating the EGCG-rich supplements should be avoided during nintedanib therapy. This finding highlights the importance of evaluating pharmacokinetic interactions before recommending flavonoid supplementation [80]. Conversely, EGCG has demonstrated promising synergistic effects in oncological settings. In pancreatic cancer models, EGCG alone or in combination with gemcitabine significantly inhibited cancer cell proliferation, migration, growth, and invasion. Mechanistically, the combination suppressed the Akt signaling pathway and modulated EMT markers, thereby enhancing gemcitabine sensitivity, anti-inflammatory, anticancer, and antitumor efficacy [81].

Nutritional interventions incorporating multiple flavonoids have also shown clinical benefits in cancer patients. A study evaluating lycopene, quercetin, bromelain, and curcumin supplementation reported improvements in key clinical parameters like reduced D-dimer levels, enhanced cytotoxic immune cell activity, and increased serum albumin concentrations. These effects suggest beneficial modulation of secondary homeostasis, immune function, and systemic inflammation in patients undergoing chemotherapy [82]. Similarly, curcumin combined with docetaxel chemotherapy exhibited antitumor and anti-angiogenic effects in patients with advanced and metastatic breast cancer, accompanied by decreased vascular endothelial growth factor (VEGF) levels. Nevertheless, the limited bioavailability of curcumin remains a significant challenge requiring further optimization [83]. In line with these findings, daily oral curcumin supplementation with FOLFOX chemotherapy was associated with improved overall survival compared with FOLFOX alone in colorectal cancer patients [84].

Beyond oncology, flavonoids have shown therapeutic effects in infectious disease settings. In severe non-ICU COVID-19 patients, quercetin administered alongside antiviral agents such as remdesivir or favipiravir significantly reduced hospitalization duration. Supplementation was associated with decreased serum levels of inflammatory and tissue damage markers, including quantitative C-reactive protein (q-CRP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and pro-inflammatory cytokines, supporting the adjunctive role of quercetin in antiviral therapy [85]. Quercetin has also demonstrated synergistic antitumor activity when combined with metformin in prostate cancer models [86]. This combination induced caspase-3 activation, reduced expression of anti-apoptotic proteins, and significantly inhibited tumor cell growth, highlighting its beneficial role in metabolic-oncologic crosstalk [86].

Luteolin has emerged as a promising chemosensitizing agent. In vitro and in vivo studies revealed that luteolin combined with paclitaxel (PTX) increased apoptotic rates and inhibited signaling pathways associated with drug resistance, thereby enhancing chemosensitivity [87]. Additionally, luteolin has been evaluated in combination with anti-programmed death receptor 1 (PD-1) immunotherapy in HCC, where it enhanced cytokine activity and immune responsiveness, suggesting immunomodulatory synergy [88]. Given the hepatotoxicity associated with sorafenib, luteolin co-treatment revealed protective effects towards normal hepatocytes by reducing oxidative stress and ferroptosis, improving GSH levels, and decreasing MDA and Fe²⁺ accumulation [89].

Wogonin has likewise demonstrated chemosensitizing effects. In pancreatic cancer models, wogonin combined with gemcitabine enhanced drug sensitivity through inhibition of Akt signaling and modulation of apoptosis-related genes, including downregulation of Bcl-2 and regulation of Bcl-2-associated agonist of death (BAD) expression [90]. Plus, wogonin and celastrol have been investigated in combination with irinotecan and melatonin in metastatic colon cancer (LOVO cell line), revealing promising antitumor effects through complementary pro-apoptotic and anti-proliferative mechanisms [91].

4. Vitamin C and Its Health-Promoting Effects: Anti-Inflammatory, Antioxidant, and Antithrombotic Potential in Cancer and Related Diseases

Vitamin C, otherwise known as ascorbic acid, is a well-established essential micronutrient with multifaceted roles in human health. Chemically, vitamin C or L-ascorbic acid, is a six-carbon lactone characterized by an enediol group and a heterocyclic ring. Its structure is defined by its ability to act as a promising reducing agent, as it can readily donate two electrons from its C2 and C3 go neutralize free radicals, a process that converts it into its oxidized but reversible form, dehydroascorbic acid [92,93,94]. Vitamin C’s (ascorbic acid) structure is provided in Figure 6.

Increasing evidence highlights its critical involvement in regulating inflammatory responses, maintaining redox homeostasis, and modulating thrombotic pathways, processes profoundly dysregulated in cancer and related diseases. [57,89,95,96]. Building on the established physiological roles of vitamin C, its unique pharmacokinetic profile, which is fundamentally distinct from that of flavonoids, must be addressed. Unlike several micronutrients, vitamin C absorption in the gastrointestinal tract is a saturable, active process mediated primarily by sodium-dependent vitamin C transporters (SVCT1 and SVCT2) [97]. At low oral doses, bioavailability is high, but as the dosage increases, the fractional absorption significantly declines, and plasma concentrations reach a steady-state “plateau” (typically around 70–80) μmol/L. Furthermore, vitamin C is thermolabile and highly sensitive to oxidative degradation, particularly when exposed to light, oxygen, or alkaline pH values [92,97]. These stability constraints necessitate encapsulation strategies when incorporated in several formulations to prevent the conversion of active ascorbic acid into the inactive dehydroascorbic acid (DHA) or further degradation of the molecule to by-products like oxalic acid [98].

These dosing limitations have profound implications for therapeutic efficacy, mainly towards the management of malignancies. The kidneys rapidly excrete excess ascorbate through glomerular filtration and regulated reabsorption. Hence, it is nearly impossible to achieve pro-oxidant, “pharmacologic” plasma concentrations, which can reach 10–20 mmol/L, via oral ingestion alone, differentiating natural from therapeutic dosing [92,93,94]. While flavonoids like isoquercetin also suffer from low bioavailability, their limitations primarily lie in their poor solubility, whereas vitamin C’s barriers are largely defined by active transport saturation and rapid renal clearance [34,92,93].

Through its encouraging antioxidant capacity, immune-modulating activity, and influence on endothelial and platelet function, ascorbic acid has emerged as a promising adjunct in the prevention and management of malignancies and cancer-associated complications. Understanding the anti-inflammatory, redox-modulating, and antithrombotic potential of vitamin C is therefore of growing interest. All mechanisms and disease-specific outcomes which will be further analyzed in the subsections below, is summarized in

Table 2. Summary of Vitamin C Treatment Strategies, Mechanistic Pathways, and Anticancer Outcomes in Various Malignancies.

Vitamin C Administration (Dose/Mode)	Study Model	Mechanisms of Action	Outcomes-Main Highlights	References
Brain Cancer
High-dose ascorbic acid (not DHA), with or without Fe3+ pre-treatment	In vitro (GBM cell lines)	ROS (↑ ROS production, ↑ intracellular labile iron)	Severe cytotoxicity and ↑ cell death	[99]
Vitamin C/E & low-dose methotrexate	In vitro (DBTRG cell line)	ROS (oxidative stress)	Synergistic anticancer effect and chemosensitization	[4]
DHA uptake via GLUT1, SVCT2 in ER	In vitro (cell lines) & In vivo (guinea pigs)	DHA transport and ↑ collagen IV (ER)	↑ GBM migration and ↑ angiogenesis/Both ↓ under vitamin C deficiency	[100]
Vitamin C & plasma-protective medium	In vivo (mice with tumors)	ROS (H2O2 → JNK pathway via AQP3)	↓ GBM cell viability, minor effect on astrocytes/Combination enhanced overall efficacy	[101]
Breast Cancer
Ascorbic acid (0.625–20 mM) alone or with α-lipoic acid (0.25–1 mM)	In vitro (human cancer cell lines) & In vivo (mice with metastatic breast cancer)	ROS (H2O2 generation)	Vitamin C reduced cell viability/Combination with ALA showed inconsistent effects	[102]
High-dose vitamin C (2 mM, 24 h)	In vitro (TNBC cell lines) & In vivo (tumor-bearing mice)	Suppression of ROS-pSTAT3, ↓ PD-L1, ↑ IL-2, ↑ T-cell activation	↓ PD-L1 expression, ↑ T-cell-mediated cytotoxicity, and ↑ CD8+ T-cells in vivo	[103]
Vitamin C & vitamin E, daily supplementation for 5 months	In vivo (randomized clinical trial)	Antioxidant enzymes, ↓ MDA, ↓ and DNA damage	↑ Antioxidant status and ↓ chemotherapy-induced toxicity	[104]
Leukemia
Grapefruit-derived nanovesicles (ELPDNVs) loaded with vitamin C (2 mM)	In vitro (chemoresistant leukemia cells)	ROS accumulation, oxidative stress (pro-oxidant action)	Selective cytotoxicity toward leukemic cells/No damage to normal cells/Encapsulation improved bioavailability and targeted delivery	[105]
Vitamin C & 3-deazaneplanocin A (DZNep)	In vitro (AML cell lines, patient-derived samples) & In vivo (mouse models)	ROS generation, apoptosis enhancement	↓ Cell viability (<20%) across AML lines/Reduced tumor size and metastasis/Vitamin C alone offered short-term cytotoxicity but no long-term effect	[106]
L-ascorbic acid (L-AA) & α-tocopherol (α-TOC) & arsenic trioxide (As2O3)	In vitro (APL cells)	↓ Nrf2, ↓ Bcl2 expression/↓ mitochondrial membrane potential/ ↑ ROS and Ca2+	Induced apoptosis via oxidative stress and mitochondrial dysfunction	[37,107]
Oral ascorbic acid supplementation (3.3 g/L)	In vivo (Tet2+/− mice)	TET2 activation (↑ 5hmC), redox regulation of Fe3+ at TET2 catalytic site	↑ TET2 activity and 5hmC; ↓ myeloid proliferation/AA restored TET2 function only in non-mutated cells	[108]
Vitamin C (10–100 μM) ± 5-azacytidine	In vitro (T-ALL cells with silenced TET2)	TET2 demethylation (↑ 5hmC), ↑ ROS, gene reactivation, ↑ HERV expression	No direct cytotoxicity with vitamin C alone/Combination induced apoptosis in TET2-silenced cells	[109]
Lymphoma
Vitamin C & complex I inhibitor (IACS-010759)	In vitro (LC cells) & In vivo (CD1 nude mice xenografts)	Redox imbalance (ROS, lipid peroxidation, ferroptosis)	Disruption of homeostasis, ↑ oxidative damage, and tumor growth suppression	[110]
Vitamin C & 5-azacytidine	In vitro (DLBCL cells)	Inflammatory pathway (ERV → cGAS-STING)	↑ Chemosensitization via cGAS-STING activation	[111]
High-dose ascorbic acid alone or with anti-PD1	In vitro (lymphoma cells) & In vivo (transgenic mouse model)	DNA demethylation, ↑ HERV, and immune pathway activation	↑ Immunogenicity, ↑ CD8+ T-cells & NK cells, and ↓ tumor growth	[112]
Myeloma
Ascorbates (AA, DHA)	In vitro (MM cells)	Mitochondrial inhibition of oxidative phosphorylation, ROS (DHA + Fe2+)	↓ Cellular respiration, ↑ mitochondrial ROS, and ↑ cytotoxicity	[113]
Pharmacologic ascorbate (PAA)—targets cells with high labile iron (LIP)	In vitro (MM cells)	ROS & mitochondrial dysfunction → caspase activation (3, 8, 9) and RIP1/RIP3 cleavage	Apoptosis and necrosis in MM cells, selective for high-iron cells	[114]
Sarcoma
Pharmacologic ascorbate, dose-dependent	In vitro (OS cancer cells)	ROS via H2O2, GSH, iron	Decreased survival, oxidative stress, and ferritin reduction	[115]
High-dose vitamin C (5–20 mM)	In vitro (OS cells) & In vivo (mouse tumor model)	ROS–Fe2+–Ca2+, mitochondrial dysfunction	Non-apoptotic cell death, reduced ATP, and inhibited tumor growth	[116]
Vitamin C (10–20 mM)	In vitro (OS-CSCs)	ROS–mitochondrial dysfunction	Nearly complete elimination of OS-CSCs	[117]
Combination vitamin C & ATO	In vitro (OS cells) & In vivo (mouse models)	↑ Bax, ↑ caspase-3, ROS, glycolysis inhibition	↓ ATO IC50, increased apoptosis, reduced migration/invasion/metastasis	[118]
Combination of vitamin C & cisplatin	In vitro (OS cells)	ROS, mitochondrial damage, DNA damage, metabolic shift (↓ OXPHOS, ↑ glycolysis)	Chemosensitization, proliferation inhibition, and enhanced cisplatin cytotoxicity	[119]
Skin Cancer
Topical vitamin C solution	Clinical trial (25 patients with low-risk BCC)	Inflammatory pathway	Lesion reduction is more effective than imiquimod, with fewer side effects, and sustained efficacy after 12 weeks	[120]
Supersaturated vitamin C solution	Case study (1 patient)	Ascorbyl radicals & H2O2, oxidative stress	Complete remission within 1 month	[121]
Vitamin C (in vitro, in vivo models)	In vitro (OSCC cells), In vivo (animals)	ROS, mitochondrial apoptosis (caspase), DNA damage, ATP depletion	Morphological changes, cell cycle arrest, and tumor growth inhibition	[122]
Vitamin C & cisplatin	In vitro (OSCC cells)	↑ ROS, ↑ DNA damage	Synergistic growth inhibition, higher DNA damage vs. single treatment	[122]
Vitamin C ≥ 3 mM	In vitro (melanoma cells), In vivo (mice)	↑ ROS, enhanced immune infiltration (CD3+ T cells)	↓ Viability <50%, reduced tumor size, and enhanced anti-PD1 (J43) effect	[123]
Vitamin C (1–10 mM) alone or with vemurafenib	In vitro (BRAF-mutant melanoma cells), In vivo (mice)	ROS (↑ H2O2), apoptosis (subG1), ↓ Glut-1	~100% cell death, reduced tumor size, enhanced vemurafenib action, and resistance reversal	[124]
Thyroid Cancer
Vitamin C & vitamin E supplementation, or combined with selenium yeast	Clinical trial (69 postoperative DTC patients under 131I therapy)	Antioxidant and cytoprotective activity	Improved parotid secretion, salivary gland protection, and best results with selenium and vitamin C combination	[125]
Oral vitamin C before or after RAIT	Clinical study in DTC patients	ROS/antioxidant defense (↑ GSH, ↓ MDA)	Pre-RAIT: ↑ GSH, strong radioprotection. Post-RAIT: ↓ MDA, moderate protective effect	[126]

↑ stands for increase, ↓ for decrease and → for “causing”.

.

4.1. Anti-Inflammatory Properties of Vitamin C

Vitamin C has been extensively investigated for its anti-inflammatory effects across a wide range of pathological conditions, including cancer, CVDs, sepsis, and viral infections. Its effects are mediated through the modulation of multiple inflammatory markers, such as IL-2, IL-10, TNF-α, and TGF-β. Intravenous vitamin C administration significantly reduced circulating levels of eotaxin, IL-4, IL-10, lymphotactin, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1β (MIP-1β), thymus and activation-regulated chemokine (TARC), TGF-β3, and TGF-β1, without a strict distinction between pro- and anti-inflammatory mediators, indicating a broad immunomodulatory rather than a unidirectional suppressive effect [127].

In vivo studies further support the immunomodulatory role of vitamin C. Treatment increased immune cell infiltration within tumor tissues, particularly CD8⁺ cytotoxic T lymphocytes, enhanced T-cell activation, elevated IL-2 secretion, and increased tumor cell killing, highlighting its ability to reinforce antitumor immune surveillance [103].

Vitamin C, also referred to as L-ascorbic acid (AA), is the biologically active L-isomer of ascorbate [128]. Its anti-inflammatory effects have been demonstrated in C57BL/6 mouse splenocytes, where AA modulated cytokine production in a stimulus-dependent manner [129]. Specifically, when combined with concanavalin A (Con A), AA reduced pro-inflammatory cytokines IL-6 and TNF-α while upregulating IL-4 and IL-10. In contrast, AA combined with LPS suppressed IL-12, indicating that vitamin C shifts cytokine balance toward an anti-inflammatory phenotype depending on the immune activation context [129].

Synergistic anti-inflammatory effects have also reported when vitamin C was combined with hydrocortisone (Hyd) in murine models of septic organ injury. This combination significantly reduced TNF-α, IL-1β, and IL-6 in RAW 264.7 macrophages compared to either treatment alone. Mechanistically, this synergy was linked to the inhibition of p38 MAPK phosphorylation and NF-κΒ p65 activation, effects that were abolished upon exposure to the ROS donor 3-nitropropionic acid (3-NP), confirming the redox-sensitive nature of this interaction [130]. In clinical settings, vitamin C alone exhibited modest anti-inflammatory effects. Patients receiving vitamin C during cardiac surgery showed no statistically significant reductions in CRP or IL-6 levels. However, when combined with vitamin B₁, a significant decrease in postoperative IL-6 levels was observed, confirming synergistic anti-inflammatory activity [131]

More recently, high-dose intravenous vitamin C (HIVC) demonstrated promising anti-inflammatory capabilities in COVID-19 patients by significantly reducing high-sensitivity CPR (hs-CRP), IL-6, and TNF-α, thereby attenuating hyperinflammatory responses [132]. In ex vivo blood samples from individuals recovering from moderate COVID-19, a single 1000 mg dose of vitamin C reduced H₂O₂ generation under elevated TNF-α exposure, mimicking both acute infection (40 ng/mL) and cytokine storm conditions (200 ng/mL). These findings confirm that vitamin C suppresses TNFα-induced oxidative stress and downstream inflammatory signaling [133]. Collectively, these data underscore the strong anti-inflammatory and immunomodulatory potential of vitamin C, supporting its role as a promising adjuvant in cancer and inflammation-related diseases.

4.2. Redox-Modulating Properties of Vitamin C

Vitamin C is one of the most propitious redox-active molecules in biological systems, exhibiting both antioxidant and pro-oxidant properties depending on concentration, cellular context, and metal availability [134]. At physiological concentrations, ascorbate primarily acts as an antioxidant, whereas at pharmacological concentrations it exerts pro-oxidant effects, particularly in cancer cells [135].

The antioxidant activity of vitamin C is mediated through direct scavenging of ROS and regulation of oxidative stress markers. In septic organ injury models, vitamin C reduced oxidative damage by decreasing MDA levels, enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and suppressing macrophage ROS generation. These effects contributed to the inhibition of redox-sensitive inflammatory pathways, including p38 MAPK signaling [130].

Vitamin C also lowered oxidation-reduction potential (ORP), a marker of oxidative stress, in the bronchoalveolar lavage fluid (BALF) of hyperoxia-exposed mice following administration of 50 mg/kg of AA [136]. In UV_B-irradiated keratinocytes, AA reduced intracellular ROS, including superoxide anions, by inhibiting xanthine oxidase and NADPH oxidase, while restoring antioxidant enzymes such as SOD, thioredoxin reductase (TrxR), and catalase (CAT). AA further increased non-enzymatic antioxidants like thioredoxin, vitamins E and C, and GSH. Through activation of the Nrf2/heme oxygenase 1 (HO-1) axis, AA enhanced phosphorylated Nrf2 and HO-1 expression while Kelch-like ECH-associated protein 1 (Keap1) and Bach1 inhibitors, reinforcing cellular defense against UV-induced oxidative stress [137].

At pharmacological concentrations, vitamin C exhibits pro-oxidant activity by generating ROS and H₂O₂. In uterine serous carcinoma cells, 4 mM AA depleted intracellular GSH [138], while in leukemic cells, 2 mM AA increased ROS levels [105]. This pro-oxidant activity is largely attributed to metal-dependent redox cycling [139,140] and extracellular H₂O₂ production [141,142].

In cancer models, AA concentrations of 1–5 mM increased intracellular ROS and enhanced carboplatin-induced DNA damage and caspase 3 activation in uterine sarcoma cancer cells [139]. In osteosarcoma cells, high-dose ascorbate generated ROS through iron-dependent oxidation to dehydroascorbic acid (DHA) via the Fenton reaction. This process disrupted mitochondrial membrane potential (MMP), suppressed oxidative phosphorylation (OXPHOS)-related gene expression, decreased adenosine triphosphate (ATP) production, and induced energy crisis-mediated cell death [116]. ROS formation also stimulated calcium release from the endoplasmic reticulum via IP3 receptors, causing mitochondrial Ca²⁺ overload and further ROS amplification.

H₂O₂-mediated cytotoxicity of ascorbate has been confirmed in liver cancer stem cells (CSCs), where pharmacological AA enhanced apoptosis through upregulation of cleaved apoptotic mediators such as cleaved poly (ADP-ribose) polymerase (PARP) and caspase-7. Importantly, catalase supplementation reversed these effects, confirming H₂O₂ dependence [143]. Similarly, in pancreatic ductal adenocarcinoma (PDAC) cells, pharmacological ascorbate-generated H₂O₂ reduced MMP-2 and MMP-9 expression, impaired invadopodia-mediated extracellular matrix (ECM) degradation, and sensitized cells to fluid shear stress, all effects being eventually reversed by CAT [141]. Additionally, ascorbate disrupted tumor iron metabolism by increasing intracellular iron and ROS levels, selectively targeting cancer cell oxidative vulnerability [142].

4.3. Antithrombotic Properties of Vitamin C

Thrombosis is a complex multiscale process involving platelet activation, aggregation, and clot formation through coordinated protein-cell signaling events. Accumulating evidence suggests that vitamin C modulates platelet function and endothelial integrity, contributing to antithrombotic activity [144].

In a clinical study involving 67 volunteers subjected to hypoxia-reoxygenation (H&R), a condition known to enhance platelet aggregation, administration of 1000 mg vitamin C significantly reduced platelet aggregation, whereas lower doses (10 and 100 nm) were ineffective [145]. In another ex vivo human platelet study, vitamin C supplementation increased intracellular platelet ascorbate concentrations from 1.2 mmol/L at baseline to 3.2 mmol/L and 15.7 mmol/L. While coagulation parameters (prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen) remained unchanged, thromboelastography (TEG) revealed prolonged R and K times, decreased α-angle, and reduced maximum amplitude at higher ascorbate concentrations (3 mmol/L vitamin C/8 days). Collagen, ADP-induced platelet aggregation, and ATP secretion remained unchanged across all groups as well. Nevertheless, high-dose vitamin C triggered the release of a plethora of eicosanoids, like T_XB₂, PGE₂, and 11-/12-/15-hydroxyicosatetraenoic acid (11-,12-,15-HETE), indicating altered platelet signaling and warranting caution with prolonged high-dose intravenous administration [146].

In murine models, ascorbate reduced platelet aggregation and P-selectin surface expression in response to thrombin, ADP, and U46619. Its inhibitory effect was more pronounced against thrombin-induced aggregation, due to interference with Gq-coupled signaling and protein kinase C (PKC) activation, pathways linked to higher ROS formation [147]. Vitamin C also exerts endothelial-protective effects relevant to thrombosis. In endothelial cells, intracellular loading with DHA attenuated thrombin-induced increases in vascular permeability by preserving cell–cell junctions. Ascorbate maintained intracellular cyclic adenosine monophosphate (cAMP) levels via activation of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, upregulating endothelial nitric oxide synthase (eNOS) activity, increasing cGMP, and preventing phosphorylation of myosin light chain (MLC) and VE-cadherin [148].

More recently, vitamin C from fresh citrus juices (orange, mandarin, and their by-products) and supplements was evaluated against platelet activation induced by the platelet-activating factor (PAF) and thrombin. Non-oxidized juice exhibited stronger anti-PAF and antithrombin activity than oxidized preparations, attributed to ascorbic acid scavenging superoxide radicals generated during platelet activation. Vitamin C showed greater inhibitory efficacy against PAF-mediated pathways, consistent with higher ROS involvement in PAF signaling. In contrast, oxidized vitamin C preparations displayed reduced anti-platelet potency with nearly twofold higher IC₅₀ values [15]. Overall, vitamin C demonstrates significant antithrombotic effects through modulation of platelet activation, endothelial function, and redox-sensitive signaling, supporting its therapeutic relevance in thrombo-inflammatory and cancer-associated coagulopathies.

4.4. Anticancer Properties of Vitamin C

4.4.1. Brain Cancer

Brain cancer, particularly glioblastoma (GB), remains one of the most aggressive and treatment-resistant malignancies, characterized by high invasiveness, chemo-resistance, and poor prognosis despite advances in surgery, radiotherapy, and chemotherapy [149]. Emerging evidence suggests that vitamin C may offer therapeutic benefits through the modulation of ROS-mediated cytotoxicity and signaling.

In vitro studies demonstrated that high-dose ascorbate, but not dehydroascorbic acid (DHA), induced marked cytotoxicity in glioblastoma cell lines via excessive ROS generation. Notably, pre-treatment with ferric iron (Fe³⁺) markedly amplified ROS production by increasing the intracellular labile iron pool, thereby enhancing oxidative damage and cancer cell death [99]. Similarly, a combination of vitamin C and vitamin E with low-dose methotrexate synergistically increased oxidative stress and cytotoxicity in DBTRG glioblastoma cells, indicating that redox imbalance can sensitize GB cells to chemotherapy [4].

Conversely, a mechanistic study revealed that GB cells preferentially uptake DHA through glucose transporter 1 (GLUT1), while GLUT3 and sodium-dependent vitamin C transporter 2 (SVCT2) are mainly intracellular, with SVCT2 localized to the endoplasmic reticulum (ER). ER-localized AA promoted collagen IV secretion, enhancing cell migration and angiogenic features. In vivo, vitamin C deficiency reduced collagen deposition, impaired vascular invasion, and disrupted glomeruloid vasculature, suggesting a co-dependent role of vitamin C in tumor progression and therapeutic vulnerability [100].

In vivo experiments combining vitamin C with plasma-conditioned medium showed enhanced cytotoxicity toward GB cells via aquaporin-3-mediated extracellular H₂O₂ uptake, activation of the Janus kinase (JNK) signaling pathway, and selective tumor cell death, with minimal effect on astrocytes. This combination highlights a promising strategy for effective GB treatment [101].

4.4.2. Breast Cancer

Breast cancer is a molecularly heterogeneous disease and remains the most common malignancy in women worldwide. Vitamin C has emerged as a promising non-toxic adjunct or alternative therapeutic agent [150].

In vitro and in vivo studies evaluating AA alone and in combination with α-lipoic acid (ALA) showed that AA (0.625–20 mM) selectively reduced cancer cell viability via H₂O₂ generation, while ALA exhibited limited independent activity. The synergy produced variable effects, underscoring the importance of optimized dosing and redox balance [102].

High-dose vitamin C also modulated immune checkpoints in TNBC. Specifically, vitamin C treatment significantly reduced programmed death-ligand 1 (PD-L1) protein and mRNA expression in a dose-dependent manner and enhanced T cell-mediated cytotoxicity (2 mM, 24 h), increased IL-2 secretion, and promoted CD8⁺ T-cell infiltration in vivo. These effects were linked to suppression of the ROS-pSTAT3 signaling axis, independent of adenosine monophosphate-activated protein kinase (AMPK) activation [103].

Clinically, co-administration of vitamin C and vitamin E during chemotherapy significantly lowered the side effects in breast cancer patients, as revealed in a randomized, 5-month, in vivo study. Notably, patients who received this vitamin C and E mix demonstrated significantly improved antioxidant enzyme activity, restored GSH levels, and reduced MDA and DNA damage, highlighting a protective role against chemotherapy-induced oxidative toxicity [104]. Overall, these findings support further clinical evaluation of vitamin C in breast cancer management.

4.4.3. Leukemia

Leukemia exhibits frequent resistance to conventional chemotherapy, prompting investigation into vitamin C’s selective cytotoxic and epigenetic effects. In an in vitro study, encapsulation of vitamin C in grapefruit-derived nanovesicles (ELPDNVs) enabled intracellular delivery (~2 mM), including ROS accumulation and selective cytotoxicity toward chemoresistant leukemia cells while sparing normal cells, thereby improving bioavailability, targeted delivery, and therapeutic specificity [105].

Combination therapy with vitamin C and the epigenetic inhibitor 3-deazaneplanocin A (DZNep) significantly reduced acute myeloid leukemia (AML) cell viability (<20%) in vitro and decreased tumor burden in vivo, primarily through enhanced ROS generation and apoptosis [106]. Similarly, co-treatment with L-ascorbic acid, α-tocopherol (α-TOC), and arsenic trioxide (As₂O₃) suppressed Nrf2 and Bcl-2 expression, disrupted mitochondrial membrane potential, increased intracellular ROS and calcium concentration, and effectively triggered apoptotic cell death [37].

Beyond redox effects, vitamin C plays a major role in ten-eleven translocation 2 (TET2)-mediated epigenetic regulation. AA supplementation restored 5-hydroxymethylcytosine (5hmC) levels, reduced myeloid cell proliferation, and enhanced TET2 activity in Tet2⁺/⁻ models by maintaining Fe³⁺ in its catalytically active redox state [108]. In TET2-silenced T-cell acute lymphoblastic leukemia (T-ALL), physiological concentration of vitamin C with 5-azacytidine increased gene reactivation, human endogenous retrovirus (HERV), and cancer cell death, identifying a targeted epigenetic strategy [109].

4.4.4. Lymphoma

Lymphomas comprise diverse malignancies with limited therapeutic options for elderly patients. It is a heterogeneous group of cancerous lymphoid tumors divided into three main categories: B-cell neoplasms, T-cell and natural killer (NK)-cell neoplasms, and Hodgkin lymphomas (HLs) [151]. Preclinical evidence supports vitamin C’s ability to enhance lymphoma treatment via redox and immune cascades [152].

In MYC-overexpressing B-cell lymphomas, vitamin C combined with IACS-010759 disrupted redox homeostasis, induced lipid peroxidation and ferroptosis, and significantly suppressed tumor growth in vivo [110]. Additionally, vitamin C enhanced the efficacy of 5-azacytidine in cisplatin-resistant diffuse large B-cell lymphoma (DLBCL) cells. The DNA methyltransferase inhibitor 5-azacytidine sensitized cells to chemotherapy by inducing endogenous retrovirus (ERV)-driven viral mimicry and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS–STING) pathway, therefore improving immunogenic cell death [111].

Similarly, in vitro, high-dose vitamin C alone and in combination with anti-PD-1 therapy led to induced DNA demethylation, increased HERV expression, and enhanced immunogenicity of lymphoma cells, without affecting their viability. In vivo, a syngeneic lymphoma mouse model combining high-dose AA with anti-PD1 therapy synergistically suppressed tumor growth and activated cytotoxic T and NK cells, as indicated by increased granzyme B expression, resulting in significant tumor suppression [112].

4.4.5. Myeloma

Multiple myeloma (MM), a cancer form regarding plasma cell accumulation in the bone marrow, with a frequent resistance to conventional therapy. MM exhibits elevated intracellular iron levels, making it particularly susceptible to vitamin C-induced oxidative stress. In this study, the ability of vitamin C to overcome this resistance through mitochondrial targeting and ROS-mediated cytotoxicity has been investigated. Ascorbate reduced cellular respiration by directly inhibiting mitochondrial oxidative phosphorylation in MM cells and by DHA, inducing a mitochondrial Fe²⁺-dependent ROS generation [113]. In a similar study, due to the higher labile iron pool (LIP) in MM tumor cells than non-tumor cells, it was hypothesized that pharmacological ascorbic acid (PAA)’s anticancer effect is dependent on LIP [114]. It was confirmed that PAA induced both necrosis and apoptosis in myeloma cells by causing mitochondrial dysfunction; triggering caspase 3, 8, and 9 activations for apoptosis; and cleaving receptor-interfering serine/threonine-protein kinases 1 and 3 (RIP1 and RIP3) for necrosis. Additionally, PAA targeted tumor cells with high iron content, revealing that iron might be the initiator of PAA cytotoxicity [114].

4.4.6. Sarcoma Cancer

Osteosarcoma (OS), the most common primary bone malignancy, has seen modest therapeutic advances. However, outcomes in metastatic disease remain poor [153]. Thus, there is a critical need to explore novel therapeutic strategies, including the use of vitamin C as a cytotoxic agent or as an adjuvant to enhance conventional treatments.

Pharmacologic ascorbate has demonstrated pronounced cytotoxicity in OS models, closely linked to iron metabolism and oxidative stress. In vitro studies showed a dose-dependent decrease in OS cell survival accompanied by increased H₂O₂ production and depleted GSH levels. Elevated labile iron pools markedly amplified ascorbate-induced toxicity, whereas iron chelation with deferoxamine (DFO) significantly attenuated oxidative damage. Additionally, ascorbate treatment reduced ferritin expression, further sensitizing cancer cells to oxidative injury [115].

Ascorbate monotherapy has also been evaluated in vitro and in vivo, revealing its capacity to induce non-apoptotic cancer cell death mediated by ROS-iron-calcium crosstalk and mitochondrial dysfunction. High-dose ascorbate (5–20 mM) significantly reduced OS cell viability in a calcium-dependent manner, as confirmed by the protective effects of Ca²⁺ chelators and CAT. Treatment also caused marked ATP depletion through disruption of mitochondrial oxidative phosphorylation, without substantially affecting glycolysis. In vivo, high-dose vitamin C notably reduced tumor growth in OS-bearing mice, highlighting mitochondrial impairment as a central mechanism [116]. Interestingly, osteosarcoma cancer stem cells (OS-CSCs) were highly sensitive to ascorbate, with near-complete elimination observed at concentrations of 10–20 mmol/L [117].

Combination therapies further underscore the therapeutic benefits of vitamin C. In OS models, co-treatment with high-dose vitamin C and arsenic trioxide (As₂O₃) significantly reduced the IC₅₀ of As₂O₃, enhanced apoptosis via Bax and caspase-3 activation, suppressed glycolytic metabolism, and reduced migration, invasion, tumor volume, and liver metastasis in vivo [118]. Similarly, combined vitamin C and cisplatin treatment elevated intracellular ROS, induced mitochondrial and DNA damage, and triggered metabolic reprogramming evident by reduced oxidative respiration and enhanced glycolysis. This combination inhibited sphere formation, suggesting improved targeting of CSC populations, and amplified cisplatin cytotoxicity dose-dependently [119]. Collectively, these findings position vitamin C as a promising adjunct for improving OS therapy.

4.4.7. Skin Cancer

Skin cancer comprises three major types: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. Vitamin C has shown therapeutic potential across all three entities. In a clinical trial involving 25 patients with low-risk BCC, topical ascorbic acid was compared in terms of effectiveness with the well-known immune-modulating agent imiquimod. After the 8-week treatment, ascorbic acid achieved superior lesion clearance with fewer adverse effects, and maintained efficacy at 12 weeks, suggesting a locally mediated inflammatory and redox-based mechanism [120].

In SCC, several studies highlight the redox-dependent cytotoxicity of vitamin C. A clinical case report described complete remission of SCC of the ear following treatment with a supersaturated ascorbic acid solution, designed to generate ascorbyl radicals and H₂O₂, thereby inducing oxidative stress [121]. In parallel, in vitro studies demonstrated that vitamin C induced severe morphological alterations in oral SCC cells, including mitochondrial caspase-dependent apoptosis, cell cycle arrest, and ATP depletion. These effects were mediated by excessive ROS generation, resulting in DNA damage and metabolic stress. In vivo, vitamin C notably inhibited oral SCC tumor growth, while combination therapy with cisplatin produced synergistic cytotoxic effects and greater DNA damage than either treatment alone [122].

In melanoma models, pharmacological ascorbate (≥3 mM) significantly decreased cell viability through ROS overproduction and enhanced immune activation. In vivo, ascorbate-treated mice exhibited reduced tumor volumes, while the combination with anti-mouse PD-1 antibody (J43) further suppressed tumor growth and increased CD3⁺ immune cell infiltration, indicating enhanced antitumor immunity [123]. In BRAF-mutated melanoma, high-dose vitamin C (1–10 mM) induced near-complete cancer cell death, increased sub-G1 apoptotic fractions, and reduced GLUT1 expression, suggesting disruption of tumor glucose metabolism. Combination therapy with ascorbate and vemurafenib resulted in significantly greater tumor regression in vivo, supporting a combinational approach to overcome BRAF inhibitor resistance [124].

4.4.8. Thyroid Cancer

The anticancer role of vitamin C in thyroid cancer remains relatively underexplored. A recent clinical study evaluated the effects of selenium yeast, vitamin E, and vitamin C, alone or in combination, on salivary gland function in differentiated thyroid cancer (DTC) patients undergoing radioiodine (¹³¹I) therapy. Among 69 postoperative patients, vitamin E combined with vitamin C significantly improved parotid gland excretory function during high-dose ¹³¹I treatment. Selenium supplementation also exhibited protective effects, while the selenium-vitamin C combination produced the most pronounced benefit, suggesting synergistic antioxidant and radioprotective activity [125].

Another study focused on the radioprotective versus radiomitigative effects of vitamin C in DTC patients receiving radioiodine ablation therapy (RAIT). Oral vitamin C administered before RAIT prevented GSH depletion and significantly reduced oxidative stress, consistent with its free radical scavenging activity. In contrast, post-RAIT administration reduced MDA levels without restoring GSH, indicating a moderate radiation-mitigative effect. Overall, vitamin C exhibited stronger radioprotective than radiomitigative efficacy in this clinical context [126].

Preclinical and clinical evidence demonstrate that vitamin C exerts significant anticancer effects through dose-dependent redox modulation, mitochondrial dysfunction, DNA damage, immune activation, and therapeutic sensitization. At low concentrations, vitamin C acts as an antioxidant, reducing ROS, MDA, and supporting endogenous defense systems such as SOD and CAT. At pharmacological doses, it functions as a pro-oxidant, generating H₂O₂ and inducing selective cancer cell death. Importantly, multiple studies indicate enhanced efficacy when vitamin C is combined with chemotherapeutic agents (e.g., arsenic trioxide, cisplatin) or epigenetic modulators, reinforcing its value in combination strategies. Flavonoids share overlapping redox, inflammatory, and signaling cascades with vitamin C, positioning them as ideal candidates for synergistic application [154]. Therefore, systematic investigation of vitamin C-flavonoid combinations may offer improved stability, bioavailability, and therapeutic efficacy across diverse cancer types.

5. Synergistic Action and Interaction Between Vitamin C and Flavonoids

Cancer, metabolic disorders, CVDs, and thrombosis are associated with amplified inflammation and oxidative stress-related manifestations, evident by the vast production of ROS and oxidized phospholipids (ox-PLs), which serve as triggers of platelet activation, endothelial dysfunction, and inflammatory gene expression [9,10,17,20,125,135].

Oxidative stress directly amplifies PAF synthesis through PAF/PAF-receptor (PAF-R)-dependent pathways, involving phospholipase Cβ (PLCβ) and MAPKs, as well as PAF-cholinephosphotransferase (PAF-CPT) and lysophosphatidylcholine acyltransferase (LPCAT). Moreover, ox-PLs and inflammatory mediators stimulate thrombin generation, collagen-related platelet activation, ADP release, and T_XA₂ synthesis via COX-2 and eicosanoid signaling. These events reinforce thrombo-inflammatory circuits, linking platelet activation with vascular inflammation and immune cell recruitment [2,17,95,96,155].

Concurrently, pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and interferon-γ (IFN-γ), further intensify this response by activating the NF-κΒ cascade. NF-κΒ activation occurs through phosphorylation and degradation of its inhibitor IκΒ, allowing NF-κΒ translocation to the nucleus and induction of inflammatory gene transcription. In parallel, TGF-β and COX-2-derived eicosanoids contribute to sustained inflammatory signaling and cellular dysfunction [2,17,95,96,133,154,155]. Environmental and dietary xenobiotics additionally activate the aryl hydrocarbon receptor (AhR), which heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT) and binds xenobiotic dioxin response elements (DREs), including Phase I detoxification enzymes such as cytochrome P450 monooxygenases, esterase, amidases, and NADPH-CYP reductases. While these enzymes facilitate xenobiotic metabolism, they can also generate ROS as by-products, further exacerbating oxidative stress [2,156,157].

Flavonoids, including quercetin, catechin, rutin, luteolin, apigenin, and curcumin, intervene at multiple nodes of this network. They directly scavenge ROS, inhibit lipid peroxidation, suppress PAF biosynthesis, and attenuate COX-2 activity and eicosanoid production. Most importantly, flavonoids inhibit platelet aggregation induced by ADP, PAF, collagen, and thrombin, thereby disrupting thrombo-inflammatory amplification loops. Interestingly, when standards of all classes of flavonoids were assessed in human platelets against all these platelet agonists and thrombo-inflammatory mediators, they all showed higher specificity against the inflammatory pathway of PAF, while when incorporated in mixed solutions they showed much higher anti-PAF efficacy in a synergistic way [154].

Moreover, molecular docking in silico analyses have also shown that flavonoids like quercetin have shown high specificity for binding on PAF-receptor, suggesting that their anti-PAF inhibitory effects take place through their antagonistic binding effect on PAF-receptor (Figure 7). At the transcriptional level, flavonoids suppress NF-κΒ activation, leading to reduced expression of pro-inflammatory cytokines and mediators [5,17,20,38,55,71,76,86,95,156].

Vitamin C acts “synergistically” with flavonoids by reinforcing redox homeostasis and modulating both inflammatory and antioxidant signaling pathways. As a promising water-soluble antioxidant, vitamin C directly neutralizes ROS and regenerates oxidized flavonoids, thereby prolonging their bioactivity. Via redox-sensitive mechanisms, vitamin C stabilizes the Keap1-Nrf2 complex, promoting Nrf2 dissociation and nuclear translocation. Activated Nrf2 binds to the antioxidant response elements (AREs) in cooperation with small Maf (sMAF) proteins, including Phase II detoxification and antioxidant enzymes like GSH S-transferases, sulfotransferases, N-acetyltransferases, GSH-Px, NADPH-generating enzymes, and HO-1, further enhancing cellular resilience against oxidative damage and suppressing inflammation-driven cancer and thrombosis [57,89,95,96].

Ultimately, the synergistic actions of vitamin C and flavonoids converge on the suppression of thrombo-inflammatory pathways, inhibition of NF-κΒ-dependent gene expression, activation of Nrf2-driven cytoprotective programs, and restoration of redox balance. Figure 8 illustrates the integrated molecular network via which flavonoids and vitamin C modulate oxidative stress, inflammation, thrombosis, and cellular detoxification in the context of chronic diseases, including CVDs, cancer, and inflammatory conditions.

Beyond the well-documented biological effects of vitamin C, its combination with flavonoids has attracted growing attention due to potential synergistic interactions that enhance antioxidant, anti-inflammatory, antithrombotic, and anticancer activities. Numerous recent studies have focused on elucidating the molecular mechanisms underlying these interactions and their therapeutic relevance across chronic inflammatory, cardiovascular, infectious, and neoplastic diseases [19,20,21,38,135,154].

A recent study evaluated the synergistic antioxidant, antithrombotic, and antiplatelet activity of vitamin C combined with flavonoids using both in vitro assays and in vivo evaluation in healthy subjects. Combined interactions were demonstrated by significantly lower half-maximal inhibitory concentration (IC₅₀) values in platelet aggregation assays when the compounds were combined, compared with each compound alone. In vivo, higher half-maximal effective concentration (EC₅₀) values were observed against platelet activation induced by three major platelet agonists, namely ADP, PAF, and thrombin, indicating enhanced inhibitory efficacy. Collectively, these findings support the use of vitamin C and flavonoids as complementary agents in the prevention and management of chronic inflammation- and thrombosis-related diseases [154].

Substantial evidence also supports synergistic anticancer effects of vitamin C when combined with quercetin. In cancer cell models, this combination induced Nrf2- mediated redox imbalance, enhancing total antioxidant capacity while simultaneously reducing cancer cell viability [96]. Additional studies showed that quercetin potentiated the anticancer activity of vitamin C through inhibition of the Akt/mTOR signaling pathway, upregulated caspase -3 activation, and enhanced apoptotic cell death [158]. Similarly, in human colorectal cancer cells, co-treatment with vitamin C and quercetin reduced cell viability and increased apoptosis more effectively than either compound alone [29].

Beyond oncology, the vitamin C-quercetin combination has been extensively investigated for antiviral and immunomodulatory effects. In murine models of H1N1 influenza infection, co-administration notably improved survival outcomes [159]. More recent studies targeting SARS-CoV-2 and other respiratory viruses demonstrated that vitamin C and quercetin exert synergistic antiviral activity, including disruption of viral replication, attenuation of inflammatory responses, and enhancement of immune function [159]. Supporting these findings, clinical and preventive studies evaluating quercetin-vitamin C-bromelain combinations in healthcare workers reported protective effects against COVID-19 infection, highlighting their promising role in immune support strategies [160]. However, despite increased plasma quercetin concentrations following combined supplementation, no significant effects on body mass or composition were observed in overweight or obese individuals, contrasting with earlier in vitro and animal data on adipogenesis modulation and basal metabolism [161]. A clinical evaluation of the synergy between rutin and vitamin C supplementation in hemodialysis patients revealed that this synergy reduced MDA (~50%) and TNF-α (~80%) values and increased HDL, leading to a significant improvement in the lipid profiles of treated patients [95].

Synergistic interactions have also been reported between vitamin C and curcumin, particularly in breast cancer models. Combined treatment enhanced intracellular vitamin C accumulation and significantly increased apoptosis compared with monotherapy, suggesting that curcumin may improve vitamin C-mediated cytotoxicity [162]. In cardiovascular contexts, flavonoid-rich hawthorn extract synergistically enhanced the antioxidant activity of vitamin C, reduced oxidative stress, normalized arterial wall structure, improved NO bioavailability, and lowered blood pressure in vivo in rat models [163]. Similarly, almond skin flavonoids exhibited combined interactions with vitamin C by protecting LDLs from oxidation, supporting their beneficial role in CVD prevention [164].

Clinical and nutritional studies further support these findings. Supplementation with orange juice rich in vitamin C and flavonoids such as hesperidin significantly improved blood lipid profiles in hypercholesterolemic patients, including increased levels of this mixture, resulting in increased high-density lipoprotein (HDL) cholesterol, decreased triacylglycerols, and a 16% reduction in the LDL/HDL ratio, with many benefits regarding dyslipidemia management [165]. Moreover, in a cluster-randomized controlled trial involving heat-exposed workers, beverages enriched with vitamin C and hawthorn-derived flavonoids notably reduced systolic and diastolic blood pressure and 8-iso-prostaglandin F₂ (PGF₂) levels, indicating reduced oxidative stress and hypertension risk [166].

More recently, luteolin combined with vitamin C and trace metals (zinc and magnesium) demonstrated a 10-fold reduction in IC₅₀ against SARS-CoV-2 3CL protease compared with vitamin C alone, underscoring the potential of multi-component synergistic formulations for antiviral therapy [167]. On the other hand, Gruber-Bzura [168] explicitly concludes that no studies support high-dose vitamin C supplementation as prophylaxis against SARS-CoV-2 in healthy subjects, whereas hypovitaminosis patients are more likely to respond to vitamin C administration. Nevertheless, Vitamin C seems to mostly provide antioxidant and antithrombotic prophylaxis against the SARS-CoV-2 thrombotic and platelet aggregatory induction, rather than an antiviral prophylaxis, and thus the relationship between vitamin C and immune system should be re-evaluated in terms of counterbalancing the effects induced by the viruses rather than inducing an antiviral effect in general.

Additionally, patent literature describes stabilized formulations of vitamin C combined with flavonoids, emphasizing improved antioxidant stability and bioefficacy [155]. Finally, the co-occurrence of vitamin C and flavonoids in fruits and vegetables reinforces their dietary relevance, as combined intake enhances antioxidant capacity and promotes synergistic biological effects associated with reduced inflammation and cardiometabolic risk [169].

Overall, current evidence, largely preclinical with limited but growing clinical support, indicates that flavonoids represent highly promising synergistic partners for vitamin C. This combination may enhance bioavailability, stability, and therapeutic efficacy across inflammatory, cardiovascular, infectious, and cancer-related conditions, warranting further well-designed clinical trials.

6. Limitations, Challenges, and Future Perspectives

Despite the extensive body of preclinical evidence supporting the synergistic biological benefits of vitamin C and flavonoids, several limitations remain underexplored. A major challenge lies in the predominance of in vitro and animal studies, which often employ supraphysiological concentrations of both vitamin C and the selected flavonoids, hence making it difficult to achieve through dietary intake or conventional oral supplementation in humans. In particular, many anticancer, antithrombotic, and anti-inflammatory effects of vitamin C depend on pharmacological concentrations that generate H₂O₂ in the extracellular space, a condition highly influenced by tissue oxygenation, metal ion availability, and antioxidant buffering capacity. Therefore, a direct translation of preclinical evidence into clinical efficacy potency remains limited [154,155,163,169,170,171].

Another critical limitation concerns the bioavailability and pharmacokinetics of flavonoids, as most of them undergo extensive liver metabolism in the intestine and liver, resulting in conjugated metabolites with altered, often undesirable biological activity. Interindividual variability in gut microbiota composition further complicates flavonoid absorption, metabolism, and systemic exposure [171,172,173,174]. Although vitamin C has been shown to stabilize certain flavonoids and regenerate their reduced forms, this hypothesis is still insufficiently characterized in terms of their in vivo synergy, particularly in human populations with diverse metabolic phenotypes [154,171,172,173,174].

Clinical evidence supporting vitamin C-flavonoid combinations is still scarce. Existing trials are either limited in number or sample size and duration, often focusing on specific biomarkers rather than clinical endpoints such as cardiovascular events, thrombosis, cancer progression, or survival [154,171,172,173,174]. Moreover, many studies use complex mixtures (e.g., fruit extracts or multi-nutrient formulations), making it difficult to attribute observed effects specifically to vitamin C-flavonoid interactions [13,25,154,175,176,177]. Another challenge lies in the dual pro-oxidant and antioxidant/redox-modulating role of vitamin C, which is complex and may vary depending on disease state, tissue microenvironment, and treatment timing, underscoring the need for precise therapeutic windows, further clinical studies, and context-specific application [16,96,139].

From a translational perspective, formulation and delivery remain significant hurdles, as several flavonoids exhibit poor solubility and stability [174], while vitamin C is easily oxidized under physiological and storage conditions [175]. Advanced delivery systems, such as nanoformulations, liposomes, and co-encapsulation strategies [175,178], as well as the integration and utilization of AI and omics technologies [179,180,181,182,183].

From the paradigms of trials against persistent infections like HIV [184] and SARS-COV-2 [160], either when solely administrating Vitamin C or in synergy with other vitamins or phytochemicals, including bioactive flavonoids [160,184], the need for future research has stemmed, which should prioritize well-designed randomized controlled trials that specifically evaluate vitamin C-flavonoid combinations, with clearly defined doses, formulations, and clinically effective endpoints. Mechanistic studies integrating redox biology, immune modulation, thrombosis, CVDs, cancer, and epigenetic regulation, alongside the integration of metabolomics, microbiome analysis, and AI-technologies, may further clarify interindividual variability and optimize personalized therapeutic strategies, building the next generation of nutraceuticals and natural remedies [154,175,178,179,180,181,182,183,184].

7. Conclusions

Vitamin C and flavonoids are biologically complementary bioactive compounds that converge on key molecular pathways regulating oxidative stress, inflammation, thrombosis, and cancer progression. Experimental evidence supports their potential synergistic actions, particularly through redox modulation, inhibition of thrombo-inflammatory signaling, and regulation of platelet- and immune-mediated processes, providing a strong mechanistic rationale for combined application in cardiovascular, oncological, and chronic inflammatory conditions.

However, most available evidence remains preclinical, with limited and heterogeneous clinical data. Translation into clinical practice will require well-designed human studies, standardized dosing strategies, optimized formulations to overcome bioavailability limitations, and careful evaluation of safety and drug–nutrient interactions. Addressing these challenges is essential to distinguish true therapeutic synergy from additive or context-dependent effects and to define the role of vitamin C–flavonoid combinations as evidence-based adjuncts in chronic disease prevention and management.