Flavonoids exhibit considerable preclinical promise through multi-target mechanisms but face translational barriers owing to poor oral bioavailability and insufficient clinical validation, so future research must prioritize rigorous multicenter randomized controlled trials with optimized formulations, comparative efficacy studies, systematic safety evaluations, and multi-omics integration.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, yet no pharmacological therapy has achieved regulatory approval. Flavonoids, plant-derived polyphenols encompassing seven structural subclasses, exhibit considerable preclinical promise through multi-target mechanisms but face translational barriers owing to poor oral bioavailability and insufficient clinical validation. This review systematically evaluates 33 structurally characterized single flavonoids for their therapeutic mechanisms, pharmacological targets, and translational prospects in MASLD, integrating evidence from cellular models, diverse rodent models, and available clinical trials. A tiered evidence classification (Levels A–C) was applied based on clinical data availability, multi-model validation, mechanistic depth, and study design rigor. Mechanistically, flavonoids restore hepatic lipid homeostasis by concurrently inhibiting SREBP-1c-mediated de novo lipogenesis and promoting PPARα-driven fatty acid β-oxidation via AMPK activation; ameliorate insulin resistance through IRS-1/PI3K/Akt signaling; attenuate hepatic inflammation by suppressing NF-κB/NLRP3 inflammasome cascades; reinforce antioxidant defenses via Nrf2/ARE-mediated induction of HO-1, SOD, and GPX4 with concomitant ferroptosis inhibition; enhance autophagic-lysosomal lipid clearance through TFEB nuclear translocation and Sirt1-dependent lipophagy; and remodel gut microbiota composition to fortify intestinal barrier integrity. Genistein, dihydromyricetin, quercetin, and kaempferol exemplify polypharmacological engagement across multiple pathways. Despite robust mechanistic evidence, oral bioavailability remains limited to 1%–5% owing to poor aqueous solubility, extensive phase II conjugation, and food-matrix interactions. Emerging strategies—carbamate prodrugs, nanoliposomes, biomimetic nanoemulsions, and colon-targeted nanoparticles—demonstrate feasibility in surmounting these barriers. Clinical evidence reveals compound-specific efficacy profiles: hesperidin reduces steatosis and transaminases; genistein improves insulin sensitivity; naringenin ameliorates lipid profiles without altering fibrosis markers. Critical appraisal identifies persistent limitations including small sample sizes, predominant reliance on male animals, short intervention durations, and absence of biopsy-confirmed endpoints. Future research must prioritize rigorous multicenter randomized controlled trials with optimized formulations, comparative efficacy studies, systematic safety evaluations, and multi-omics integration to bridge the translational gap toward evidence-based flavonoid therapeutics for MASLD.
Metabolic dysfunction-associated steatotic liver disease (MASLD) develops when hepatic lipid acquisition and synthesis exceed the capacity for oxidation and very-low-density lipoprotein export. Flavonoids act on several components of this network, yet their therapeutic development is constrained by poor aqueous solubility, extensive intestinal and first-pass metabolism, variable activity of circulating metabolites, and limited information on hepatic exposure. Experimental studies link representative flavonoids to AMPK–SREBP-1c and PPARα signaling, mitochondrial quality control, Nrf2-dependent redox defense, inflammatory pathways, and the gut–liver axis. By contrast, the available randomized trials of quercetin, hesperidin, anthocyanins, green-tea catechins, EGCG, and soy isoflavones show at most modest changes in liver fat or biochemical markers and do not demonstrate metabolic dysfunction-associated steatohepatitis (MASH) resolution or fibrosis regression. Liposomal, lipid-based, polymeric, and nanocrystal formulations have improved dissolution, systemic exposure, or liver distribution in preclinical models, but comparative pharmacokinetics, chronic safety, manufacturability, and clinical efficacy remain poorly defined. The evidence therefore supports viewing flavonoids as formulation-dependent investigational candidates rather than established MASLD therapies. Progress will depend on chemically standardized products, exposure–response studies, clinically relevant models, and adequately powered trials using validated imaging or histological endpoints.
This review summarizes recent advances in the use of natural products for the treatment of renal fibrosis, with a particular focus on their underlying molecular mechanisms, current status of clinical translation, and the challenges that remain.
Yan Liu, Lei Gao, Hao Xu et al.· Renal Failure· 0 citations
BACKGROUND
Recent years, natural plant components, especially flavonoids, known for their anti-inflammatory, antioxidant, and immunomodulatory properties, show potential in the treatment of rosacea.
OBJECTIVE
This review aims to synthesize and critically evaluate the advancements in the therapeutic application of flavonoid compounds for rosacea, encompassing both clinical studies and experimental outcomes from in vitro and in vivo models, thereby providing a reference for future research directions and treatment strategies.
METHODS
A systematic literature search was conducted in Web of Science, PubMed, ScienceDirect, Wiley, and Embase up to 26 September 2024, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a comprehensive set of rosacea- and flavonoid-related keywords.
RESULTS
In vitro studies indicate that flavonoids modulate the Sirtuin 3 (SIRT3)-Superoxide Dismutase 2 (SOD2)-Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis and suppress inflammatory mediators such as Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-17 (IL-17). They also regulate Vascular Endothelial Growth Factor (VEGF), Transient Receptor Potential Vanilloid 1 (TRPV1), Kallikrein-related Peptidase 5 (KLK5), and Protease-Activated Receptor 2 (PAR2), contributing to neurogenic inflammation control and skin barrier repair. In vivo models show reduced inflammatory infiltration and angiogenesis. Early clinical studies suggest good safety profiles and potential synergy with standard therapies, though larger Randomized Controlled Trials (RCTs) are needed.
CONCLUSIONS
Flavonoids exert multi-target effects in rosacea via anti-inflammatory and vascular-modulating mechanisms. Future research should prioritize advanced neuroimmune models, enhanced delivery systems, and patient stratification approaches to optimize clinical application.
Meng Chen, Xinru Hu, Bowen Tan et al.· Immunopharmacology and immun...· 0 citations
Hepatic metabolic dysfunction is a central feature of diabetes mellitus and metabolic syndrome and plays a major role in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This review aims to summarize and critically analyze the effects of naringin (NAR), a citrus-derived flavonoid, on hepatic metabolic dysfunction associated with metabolic disorders, with particular emphasis on underlying molecular mechanisms and translational relevance. Experimental and clinical evidence indicates that NAR exerts hepatoprotective effects through the modulation of multiple interconnected pathways involved in metabolic injury, including oxidative stress, inflammatory signaling, lipid homeostasis, mitochondrial function, and autophagy. These effects are mediated, at least in part, through AMPK-, PPARα-, and NF-κB- related signaling pathways. Despite the consistent beneficial effects observed in preclinical models, significant discrepancies remain between experimental efficacy and clinically achievable concentrations, highlighting important pharmacokinetic and pharmacodynamic limitations. Emerging strategies aimed at improving bioavailability and therapeutic targeting may help bridge this translational gap. In conclusion, current evidence supports NAR as a promising multitarget therapeutic candidate for hepatic metabolic dysfunction; however, further studies addressing pharmacological optimization and clinical translation are required to fully establish its therapeutic potential.
María Paula Combina Herrera, G. N. Ávila Sabattini, G. Picotto et al.· European Journal of Pharmaco...· 0 citations
Age-related and chronic ocular diseases share common underlying mechanisms including oxidative stress, low-grade inflammation, mitochondrial dysfunction, and neurodegeneration. In parallel with advances in conventional therapies, interest in bioactive compounds derived from dietary sources (nutraceuticals) has increased due to their multiple molecular effects and potential to modulate the pathways leading to ocular disease. In this work, the current evidence for major classes of nutraceuticals, including carotenoids, polyphenols, organosulfur compounds, and other plant-derived metabolites was examined, with emphasis on their pharmacodynamic properties, mechanisms of action, and clinical relevance in ocular health. Mechanistic insights from in vitro and animal models were integrated with findings from clinical studies, highlighting molecular targets such as Nrf2-mediated antioxidant responses, NF-κB-driven inflammation, angiogenic signalling, and mitochondrial function. Carotenoids including lutein and zeaxanthin show the most consistent clinical evidence, particularly in increasing macular pigment optical density and reducing progression to advanced macular degeneration. In contrast, other carotenoids and most polyphenols including flavonoids, curcumin, and resveratrol demonstrate promising anti-inflammatory and anti-angiogenic effects primarily supported by preclinical data, with limited and heterogeneous clinical validation. Overall, current evidence suggests that nutraceuticals may have different effects and applicability in managing ocular diseases, although the majority of compounds discussed remain supported only by mechanistic and preclinical data, instead of clinical evidence. Future progress will require rigorously designed clinical studies, improved pharmacokinetic characterization, and precise stratification of patient populations to establish their therapeutic efficacy and relevance.
Margherita Paracini, A. Radwan, Gregorio Peron· Journal of Nutritional Bioch...· 0 citations
Diabetes mellitus results from insulin resistance, progressive pancreatic β-cell dysfunction, dysregulated hepatic and adipose metabolism, oxidative stress, and inflammation. Plant-derived compounds can modulate several of these processes, yet pharmacological breadth does not necessarily produce a reproducible therapy. This critical narrative review links phytochemical identity and product composition to intestinal carbohydrate digestion, insulin secretion, hepatic glucose production, GLUT4 trafficking, AMPK and PPARγ signaling, the incretin–DPP-4 axis, renal glucose handling, and diabetic organ injury. Alkaloids, flavonoids, phenolic acids, tannins, saponins, and polysaccharides are considered alongside evidence concerning nephropathy, neuropathy, ocular disease, hepatopathy, and cardiomyopathy. Controlled human studies provide product-specific signals, particularly for chemically defined berberine preparations and mulberry alkaloids, whereas most other interventions remain supported by small, short, or chemically undercharacterized trials. The strongest candidates are those for which defined chemistry, plausible exposure, mechanism, and controlled clinical findings converge. Progress requires authenticated raw material, validated analytical fingerprints, pharmacokinetic and toxicological characterization, herb–drug interaction testing, and trials using the same standardized product. These interventions should remain supervised adjuncts or drug-discovery leads rather than substitutes for established diabetes treatment.
Pirscoveanu Denisa Floriana Vasilica, D. Traşcă, A. Kamal et al.· Molecules· 0 citations
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