The Biological Effects and Mechanisms of Fisetin on Hepatotoxicity, Liver Injury, and Liver Fibrosis: A Systematic Review

Abstract

Background: Liver disease is a common cause of death worldwide. Objectives: This study aims to investigate the effects and mechanisms of Fisetin on hepatotoxicity, liver injury, and liver fibrosis. Methods: We adhered to the PRISMA 2020 guidelines in this systematic review. Our search used MeSH keywords encompassed Embase, PubMed, Web of Science, Scopus, and Cochrane Library for articles published before March 2, 2024. Relevant data was extracted from the publications, meticulously recorded in a standard form, and subsequently reviewed for outcomes and mechanisms. Results: Fisetin protects hepatocytes from oxidative stress by neutralizing free radicals (O2 −and H2O2), reduces oxidative stress, prevents lipid peroxidation, and increases endogenous antioxidants. It also reduces inflammation via lowering the production of tumor necrosis factor α (TNF-α), interleukins (IL)1α, IL-6, IL-18, IL-1β suppressing nuclear factor kappa B (NF-κB) activation, and cyclooxygenase- 2 (COX-2), inducible nitric oxide synthase (iNOS) inhibition, reducing monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), NLR family pyrin domain-containing 3 (NLRP3) inflammasome and interferon-gamma (IFN‐γ). Moreover, it inhibited apoptosis-modulated enzyme activity and detoxification enzymes via modulating the activity of cytochrome P450 and Phase II detoxification enzymes. Fisetin prevented fibrosis by inhibiting the activation of hepatic stellate cells (HSCs), attenuating extracellular matrix (ECM) remodeling-associated genes, and suppressing transforming growth factor-β (TGF-β) signaling pathway and attenuating collagen production. It decreased lipid accumulation and liver function tests. Conclusion: In vivo and in vitro studies indicated that Fisetin can enhance detoxification, attenuate liver injury, and reduce fibrosis, which helps maintain liver health.