Hesperidin alleviates nonalcoholic steatohepatitis by inhibiting cellular senescence through regulation of the BMP4/P21 pathway

• Hesperidin alleviates NASH. • Hesperidin alleviates NASH by inhibiting hepatocellular senescence. • Hesperidin inhibits hepatocyte senescence by modulating BMP4/P21axis. Nonalcoholic steatohepatitis (NASH) characterized by liver cellular damage induced by high-fat diets. Hesperidin (HDN) has demonstrated potential in mitigating such damage. However, the specific mechanisms of HDN in NASH remain to be elucidated. Initially, we modeled free fatty acid (FFA)-induced steatosis in vitro experiments. Measuring pertinent cellular fatty degeneration markers. Subsequently, a transcriptomics approach was employed to investigate the impact of HDN on gene expression profiles within the FFA-induced HepG2 cell fatty degeneration model. Western blot was used for verification. Furthermore, BMP4 was silenced in HepG2 cells to evaluate HDN's regulatory effect on BMP4. In vivo experiments establishing a NASH mouse model and administering HDN to assess its therapeutic potential. HDN intervention effectively reduced NEFA levels in cell supernatant and TG levels within cells. It also decreased the area of lipid droplets in cells. Transcriptomics analysis revealed that HDN intervention influenced the expression of genes associated with the TGF-beta signaling pathway and cellular senescence pathway. HDN intervention significantly decreased the SA-β-gal activity. Moreover, silencing BMP4 attenuated the therapeutic effects of HDN intervention on FFA-induced HepG2 cell injury. In vivo experiments further demonstrated that HDN intervention effectively reduced body weight and liver index in NASH mice. It also lowered serum ALT and AST activities, as well as liver tissue TG levels. Our experiments have conclusively demonstrated that HDN intervention effectively mitigates liver tissue injury and hepatocyte senescence. The mechanism underlying HDN's efficacy appears to involve BMP4 activation, P21 inhibition, thereby suppressing hepatocyte senescence and ultimately ameliorating NASH.