GenX induces cochlear hair cell injury via System Xc--Gpx4-Fsp1 ferroptosis axis
10.16016/j.2097-0927.202507094
- VernacularTitle:GenX通过System Xc--Gpx4-Fsp1铁死亡轴诱导耳蜗毛细胞损伤
- Author:
Zhengwei LIANG
1
;
Huihui HONG
;
Wei YUAN
Author Information
1. 西南医科大学附属医院耳鼻咽喉头颈外科
- Keywords:
ferroptosis;
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate;
phospholipid hydroperoxide glutathione peroxidase;
ferroptosis suppressor protein 1;
cochlear hair cells
- From:
Journal of Army Medical University
2025;47(21):2652-2662
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the role and mechanism of ferroptosis in cochlear hair cell injury induced by exposure to ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate(GenX).Methods Mouse cochlear hair cell line HEI-OC1 was assigned to control,GenX,ferrostatin-1(Fer-1),and GenX+Fer-1 groups.CCK-8 assay was used to assess the cytotoxicity of GenX and the rescue effect of Fer-1 co-treatment.Western blotting and qRT-PCR were employed to measure the protein and transcriptional expression of ferroptosis markers,cochlear function indicators,blood labyrinth barrier markers,and ferroptosis-related pathway.FerroOrange,Bodipy(C11),mitochondrial membrane potential assay kit(JC-1),and adenosine triphosphate(ATP)assay were applied to detect Fe2? accumulation,lipid peroxidation,mitochondrial membrane dysfunction,and cellular ATP levels,respectively.Results Exposure to 200 μmol/L GenX for 12 h significantly reduced the viability of HEI-OC1 cells(P<0.01),down-regulated the protein levels of glutathione peroxidase 4(Gpx4),solute carrier family 7 member 11(Slc7a11),and ferroptosis suppressor protein 1(Fsp1)(P<0.05),whereas up-regulated acyl-coa synthetase long-chain family member 4(Acsl4)(P<0.01),and decreased the expression of cochlear hair-cell function genes and blood labyrinth barrier genes(P<0.05).These changes were accompanied with Fe2+accumulation,elevated lipid peroxidation,mitochondrial membrane damage,and reduced ATP production(P<0.001).Addition of Fer-1 restored cell viability(P<0.05),restored the expression of ferroptosis related proteins(P<0.05),and improved the expression of several hair-cell function and blood labyrinth barrier genes(P<0.05).In parallel,the GenX+Fer-1 group exhibited reduced Fe2? accumulation,lower lipid peroxidation,attenuated mitochondrial membrane damage,and increased ATP level(P<0.001).Conclusion GenX induces iron-metabolism dysregulation and lipid peroxidation,and then leads to differentiation impairment of cochlear hair cells and barrier functions via the ferroptotic System Xc?-Gpx4-Fsp1 axis.
