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ACS Omega

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Perfluorooctanoic Acid Induces Ferroptosis in Hepatocytes via Oxidative Stress and AKT/GSK3β/β-Catenin Pathway Disruption

Published:13 January 2025 DOI: 10.1021/acsomega.4c07198 PMID: 39895706
Yuan Feng,?Bin Lu,?Yongheng Huang,?Hui Wang,?Jianliang Xu,?Nan Lin

Abstract

Perfluorooctanoic acid (PFOA), a typical environmental contaminant, has been observed in tissue samples of various diseases, including liver cancer. PFOA can lead to hepatotoxicity, but the underlying molecular mechanism remains unclear. Our results showed that PFOA significantly inhibited HL-7702 (L02) and MIHA cell viability in a time- and dose-dependent manner. Furthermore, PFOA could cause oxidative stress, mitochondrial injury, and ferroptosis. In addition, PFOA upregulated the levels of malondialdehyde and glutathione/oxidized glutathione and downregulated the expressions of SLC7A11 and GPX4, which refer to typical phenotypes of ferroptosis. PFOA suppressed phosphorylation of signaling cascades AKT/GSK3β/β-catenin, indicating the signal pathway might be related to ferroptosis. In order to prove the above hypothesis, the Wnt signaling pathway activator chir99021 was used and the result revealed that PFOA-induced inhibition of p-AKT and its downstream effectors p-GSK3β, SLC7A11, and GPX4 was counteracted. On the other hand, the inhibitor of p-AKT, Ly294002, strengthened PFOA's regulatory actions on these factors. Overall, our results suggest that PFOA can lead to liver cell injury by inducing oxidative stress and ferroptosis. The effects are conferred through the regulation of the AKT/GSK3β/β-catenin signaling cascades.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
LY 294002 Hydrochloride 154447-36-6 C19H17NO3 404 suppliers $12.00-$3350.00
CHIR-99021 252917-06-9 C22H18Cl2N8 340 suppliers $28.00-$4401.00
CHIR-99021 252917-06-9 C22H18Cl2N8 340 suppliers $28.00-$4401.00
CHIR-99021 252917-06-9 C22H18Cl2N8 340 suppliers $28.00-$4401.00
CHIR-99021 252917-06-9 C22H18Cl2N8 340 suppliers $28.00-$4401.00

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