@article{LIANG2025, 
author = {Zhengwei LIANG and Huihui HONG and Wei YUAN},
title = {GenX induces cochlear hair cell injury via System Xc--Gpx4-Fsp1 ferroptosis axis},
year = {2025},
journal = {Journal of Army Medical University},
volume = {47},
number = {21},
pages = {2652-2662},
keywords = {ferroptosis, ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, phospholipid hydroperoxide glutathione peroxidase, ferroptosis suppressor protein 1, cochlear hair cells},
url = {https://www.sciopen.com/article/10.16016/j.2097-0927.202507094},
doi = {10.16016/j.2097-0927.202507094},
abstract = {ObjectiveTo 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).MethodsMouse 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.ResultsExposure 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).ConclusionGenX 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.}
}