Title: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
Volume: 31
Issue: 19
关键词:
肝纤维化、铁下垂、衰老、HIF-1α、姜黄酚、铁离子。
摘要:
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.
