Curcumol inhibits ferritinophagy to restrain hepatocyte senescence through YAP/NCOA4 in non‐alcoholic fatty liver disease

OBJECTIVES: In recent years, cellular senescence has attracted a lot of interest in researchers due to its involvement in non‐alcoholic fatty liver disease (NAFLD). However, the mechanism of cellular senescence is not clear. The purpose of this study was to investigate the effect of curcumol on hepatocyte senescence in NAFLD and the molecular mechanisms implicated. MATERIALS AND METHODS: LVG Golden Syrian hamsters, C57BL/6J mice and human hepatocyte cell line LO2 were used. Cellular senescence was assessed by analyses of senescence marker SA‐β‐gal, p16 and p21, H3K9me3, γ‐H2AX and telomerase activity. RESULTS: The results showed that curcumol could inhibit hepatocyte senescence in both in vivo and in vitro NAFLD models, and the mechanism might be related to its regulation of ferritinophagy and subsequent alleviation of iron overload. Moreover, overexpression of nuclear receptor coactivator 4 (NCOA4) weakened the effect of curcumol on ferritinophagy‐mediated iron overload and cellular senescence. Furthermore, we demonstrated that curcumol reduced the expression of NCOA4 by Yes‐associated protein (YAP). In addition, depression of YAP could impair the effect of curcumol on iron overload and cellular senescence. CONCLUSION: Our results clarified the mechanism of curcumol inhibition of hepatocyte senescence through YAP/NCOA4 regulation of ferritinophagy in NAFLD. These findings provided a promising option of curcumol to regulate cellular senescence by target YAP/NCOA4 for the treatment of NAFLD.