Mechanistic Analysis of Fisetin in Liver Diseases and Its Potential Therapeutic Application in IFALD—A Review of In Vitro and In Vivo Studies

Abstract

Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a naturally occurring flavonol in fruits and vegetables. It exhibits diverse biological activities, including anti-inflammatory, antioxidant, senolytic, and lipid-lowering properties. This review explores the molecular mechanisms underlying fisetin’s hepatoprotective effects and evaluates its potential application in Intestinal Failure-Associated Liver Disease (IFALD), a severe complication associated with total parenteral nutrition (TPN). IFALD is characterized by inflammation, cholestasis, steatosis, oxidative stress, and dysregulated lipid and bile acid metabolism. Fisetin modulates several key signaling pathways, including NF-κB, Nrf2, AMPK, and SIRT1, leading to reduced inflammatory cytokine expression, enhanced antioxidant defenses, and improved lipid homeostasis. Fisetin shows potential anti-fibrotic and microbiota-modulating effects. More importantly, fisetin is recognized as a potent senolytic agent, selectively activating pro-apoptotic pathways in senescent cells, which are known sources of inflammation and tissue damage. However, despite its promising pharmacological profile, the poor bioavailability of fisetin remains a significant limitation, particularly for parenteral use. Emerging drug delivery systems such as liposomes and nanoparticles offer potential solutions. Given its broad spectrum of beneficial effects and favorable safety profile, fisetin represents a compelling candidate for future studies in the prevention and management of IFALD.