Fisetin attenuates CCl₄-induced liver fibrosis through modulation of TGF-β1/Smad3 and p53/Bax/Bcl-2 signaling pathways.

Liver fibrosis arises from a sustained imbalance between oxidative stress, cell death, and matrix deposition. Using the carbon tetrachloride (CCl4) mouse model, we show that the dietary flavonoid, fisetin orchestrates a broad hepatoprotective program that blunts this cascade. Male C57BL/6 mice received CCl4 for six weeks, without/with daily fisetin at 50 or 100 mg/kg. Co-treatment with fisetin preserved body weight and lowered the liver index, and markedly attenuated biochemical injury, reducing serum ALT, AST, ALP, GGT, and TBIL while restoring total protein and albumin levels. Fibrogenic burden also decreased, as evidenced by lower circulating PIIINP, reduced hepatic hydroxyproline, as well as reduced expression of COL1A1 and α-SMA. Histology mirrored these improvements: necrosis, inflammation, and collagen accumulation were diminished, with Masson's trichrome and Sirius Red staining revealing dose-dependent normalization of liver architecture. Mechanistically, fisetin restored redox homeostasis (higher TAC, GSH, SOD, CAT, and GPx; lower MDA and TOS) and re-engaged the Nrf2/HO-1 axis at mRNA and protein levels, while simultaneously suppressing profibrotic TGF-β1/Smad3 signaling, including p-Smad3. In parallel, fisetin shifted the apoptotic tone toward cytoprotection, decreasing p53, phospho-p53, and Bax, while increasing Bcl-2, along with decreasing caspase 3/7 activity. These effects were consistently stronger at 100 mg/kg, indicating a dose-response. Together, these data position fisetin as a multifaceted anti-fibrogenic and antioxidant agent that preserves liver structure and function under toxic injury, supporting its candidacy for evidence-based phytotherapeutic strategies against chronic liver disease. According to this data, the Nrf2/HO-1, TGF-β1/Smad3, and p53/Bax/Bcl-2 axes are the main pathways modulated by fisetin intervention.