Glutathione peroxidase 4 (GPX4) as an oncogenic factor in human tumors: a pan-cancer analysis.

[UNLABELLED] We conducted an integrated pan-cancer analysis to characterize the expression profile, clinical relevance, immune associations, and cellular localization of glutathione peroxidase 4 (GPX4) across human cancers by integrating transcriptomic, proteomic, clinical, immune, and single-cell datasets. GPX4 was frequently upregulated at the mRNA level across multiple solid tumors, whereas proteomic analyses revealed reduced expression in primary tumors but progressive upregulation with advancing pathological stage in selected cancer types. Elevated GPX4 expression was significantly associated with adverse overall or disease-free survival in colorectal, stomach, adrenocortical, prostate, and uveal cancers, while an opposite prognostic pattern was observed in thyroid cancer. Immune deconvolution analyses demonstrated that GPX4 expression correlated positively with cancer-associated fibroblast infiltration and distinct immune checkpoint and T/NK-cell contexts across cancers. Single-cell transcriptomic analyses consistently localized GPX4 expression predominantly to malignant epithelial cells, with secondary expression in stromal fibroblasts and minimal expression in immune compartments. In vitro experiments further confirmed increased GPX4 expression and enhanced proliferative capacity in tumor cell lines compared with normal epithelial counterparts. Collectively, these results identify GPX4 as a context-dependent, tumor-cell-intrinsic regulator with prognostic and immunological relevance across cancers, supporting its potential as a biomarker and therapeutic vulnerability in selected tumor types.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s13205-026-04733-y.