Flavonoids in MASLD: preclinical mechanisms, pharmacological targets, and translational challenges.

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.