Peroxiredoxin 4 suppresses ferroptosis in esophageal squamous cell carcinoma by activating the phosphoinositide 3-kinase  signaling pathway.

Peroxiredoxin 4 (PRDX4) has been found to be upregulated and verified to play protective roles against oxidative stress in various tumors. However, its exact function and underlying molecular mechanisms in esophageal squamous cell carcinoma (ESCC) remain unclear. The aim of the present study was to evaluate the roles of PRDX4 in ferroptosis of ESCC cells and elucidate its potential molecular mechanisms. Bioinformatics analysis, western blotting and reverse transcription-quantitative PCR confirmed that PRDX4 was markedly upregulated in ESCC samples and cells. The close association of PRDX4 with lymph node metastasis and TNM staging was identified, and PRDX4 may be an independent prognostic marker for patients with ESCC. Furthermore, PRDX4 depletion inhibited the proliferation and invasion of ESCC cells, whereas PRDX4 overexpression had the opposite effect. Notably, PRDX4 knockdown promoted ferroptosis by increasing malondialdehyde and lipid peroxidation levels, and decreasing glutathione levels, coupled with decreased expression of glutathione peroxidase 4 and solute carrier family 7 member 11, and increased expression of prostaglandin-endoperoxide synthase 2. However, PRDX4 overexpression showed opposite effects, which were partly reversed by the ferroptosis inhibitor, ferrostatin-1 and the inducer erastin. Most crucially, PRDX4 depletion-mediated inactivation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway could be rescued by 740 Y-P (a PI3K activator), whereas PRDX4 overexpression triggered the activation of the PI3K/AKT signaling pathway, which could be reversed by the PI3K inhibitor LY294002. Collectively, the data suggest that PRXD4 suppresses ferroptosis in ESCC cells by activating the PI3K/AKT signaling pathway, suggesting that targeting PRDX4 may be a novel strategy for treating patients with ESCC.