Natural Flavonoids as Potential Modulators of Liver Fibrosis: A Review of Mechanisms and Therapeutic Targets

Liver fibrosis is a pivotal stage in the progression of chronic liver disease to cirrhosis or hepatocellular carcinoma, driven by persistent activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Emerging evidence indicates that dietary flavonoids, natural bioactive compounds with broad availability and multi-target regulatory potential, exert protective effects against liver fibrosis through pleiotropic mechanisms. This review systematically describes the pharmacological mechanisms by which flavonoids mitigate liver injury, including regulation of lipid metabolism, suppression of inflammatory responses, and inhibition of fibrogenesis. Furthermore, we focus on elaborating the specific pathways by which flavonoid monomers induce cell death and regulate cell states, and further explore how these compounds regulate macrophage polarization, protect hepatic sinusoidal endothelial cells, and inhibit pathological angiogenesis. Finally, we examine recent advances in nano-delivery systems and co-administration strategies designed to address clinical challenges such as poor bioavailability and rapid metabolism. In conclusion, natural flavonoids hold promise for anti-liver fibrosis therapy. This review provides a theoretical foundation for developing effective, targeted natural therapies for hepatic fibrosis and highlights that future research requires mechanism-driven research, formulation innovation, and clinical validation to enable personalized treatment.