Modulation of the HIF-1α-NCOA4-FTH1 Signaling Axis Regulating Ferroptosis-induced Hepatic Stellate Cell Senescence to Explore the Anti-hepatic Fibrosis Mechanism of Curcumol

Introduction: Senescence of activated hepatic stellate cells (HSC) reduces extracellular matrix expression to reverse liver fibrosis. Ferroptosis is closely related to cellular senescence, but its regulatory mechanisms need to be further investigated. The iron ions weakly bound to ferritin in the cell are called labile iron pool (LIP), and together with ferritin, they maintain cellular iron homeostasis and regulate the cell's sensitivity to ferroptosis. Methods: We used lipopolysaccharide (LPS) to construct a pathological model group and divided the hepatic stellate cells into a blank group, a model group, and a curcumol 12.5 mg/L group, a curcumol 25 mg/L group, and a curcumol 50 mg/L group. HIF-1α-NCOA4- FTH1 signalling axis, ferroptosis and cellular senescence were detected by various cellular molecular biology experiments. Result: We found that curcumol could induce hepatic stellate cell senescence by promoting iron death in hepatic stellate cells. Curcumol induced massive deposition of iron ions in hepatic stellate cells by activating the HIF-1α-NCOA4-FTH1 signalling axis, which further led to iron overload and lipid peroxidation-induced ferroptosis. Interestingly, our knockdown of HIF-1α rescued curcumol-induced LIP and iron deposition in hepatic stellate cells, suggesting that HIF-1α is a key target of curcumol in regulating iron metabolism and ferroptosis. We were able to rescue curcumol-induced hepatic stellate cell senescence when we reduced LIP and iron ion deposition using iron chelators. Conclusion: Overall, curcumol induces ferroptosis and cellular senescence by increasing HIF-1α expression and increasing NCOA4 interaction with FTH1, leading to massive deposition of LIP and iron ions, which may be the molecular biological mechanism of its anti-liver fibrosis.