Flavonoids for MASLD: Hepatic Lipid Targets, Biopharmaceutic Barriers, and Formulation Strategies

Abstract

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.