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

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.Here, we report that curcumol can induce HSC senescence by promoting HSC ferroptosis. Curcumol induces massive deposition of iron ions in HSC through activation of the HIF-1α-NCOA4-FTH1 signaling axis, which further leads to the development of iron overload and lipid peroxidation-induced ferroptosis. Interestingly, our knockdown of HIF-1α rescued curcumol-induced LIP and iron ion deposition in HSC, suggesting that HIF-1α is a key target of curcumol in regulating iron ion metabolism and ferroptosis.When we use iron chelators to reduce LIP and iron ion deposition, we rescue curcumol- induced HSC senescence, suggesting that iron ions may be a key mechanism of curcumol-induced cellular senescence.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.