Central role of Sigma-1 receptor in ochratoxin A-induced ferroptosis

Ochratoxin A (OTA), a secondary fungal metabolite known for its nephrotoxic effects, is prevalent in various feeds and food items. Our recent study suggests that OTA-induced nephrotoxicity is linked to the Sigma-1 receptor (Sig-1R)-mediated mitochondrial pathway apoptosis in human proximal tubule ep...

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Bibliographic Details
Published in:Archives of toxicology 2024-10, Vol.98 (10), p.3323-3336
Main Authors: Chen, Wenying, Han, Lingyun, Yang, Ruiran, Wang, Hongwei, Yao, Song, Deng, Huiqiong, Liu, Shuangchao, Zhou, Yao, Shen, Xiao Li
Format: Article
Language:English
Subjects:
Apoptosis
Arachidonate 5-lipoxygenase
Autophagy
Biomedical and Life Sciences
Biomedicine
Cell death
Cell viability
Environmental Health
Ferritin
Ferroptosis
Glutathione
Glutathione peroxidase
Lipid peroxidation
Lipids
Lipoxygenase
Metabolites
Molecular Toxicology
Occupational Medicine/Industrial Medicine
Ochratoxin A
Peroxidase
Peroxidation
Peroxiredoxin
Pharmacology/Toxicology
Proteins
Receptors
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Summary:Ochratoxin A (OTA), a secondary fungal metabolite known for its nephrotoxic effects, is prevalent in various feeds and food items. Our recent study suggests that OTA-induced nephrotoxicity is linked to the Sigma-1 receptor (Sig-1R)-mediated mitochondrial pathway apoptosis in human proximal tubule epithelial-originated kidney-2 (HK-2) cells. However, the contribution of Sig-1R to OTA-induced nephrotoxicity involving other forms of regulated cell death, such as ferroptosis, remains unexplored. In this investigation, cell viability, malondialdehyde (MDA) levels, glutathione (GSH) levels, and protein expressions in HK-2 cells treated with OTA and/or Ferrostatin-1/blarcamesine hydrochloride/BD1063 dihydrochloride were assessed. The results indicate that a 24 h-treatment with 1 μM OTA significantly induces ferroptosis by inhibiting Sig-1R, subsequently promoting nuclear receptor coactivator 4 (NCOA4), long-chain fatty acid-CoA ligase 4 (ACSL4), arachidonate 5-lipoxygenase (ALOX5), autophagy protein 5 (ATG5), and ATG7, inhibiting ferritin heavy chain (FTH1), solute carrier family 7 member 11 (SLC7A11/xCT), glutathione peroxidase 4 (GPX4), peroxiredoxin 6 (PRDX6), and ferroptosis suppressor protein 1 (FSP1), reducing GSH levels, and increasing MDA levels ( P  
ISSN:0340-5761
1432-0738
1432-0738
DOI:10.1007/s00204-024-03805-3