Elevated ferroptosis is associated with elevated T cells in patients with heat stroke.

backgroundHeat stroke is the most severe heat-related illness, characterized by an inflammatory response, oxidative stress, ferroptosis, and immune dysfunction. However, the broader role of ferroptosis in the pathophysiological processes of heat stroke remains unclear, and its potential connection with immune regulation has not yet been fully elucidated. This study uses bioinformatics analysis of heat stress datasets and molecular validation in patient samples to investigate key signaling pathways altered in heat stress (GSE90763) and validate their associations in heat stroke patients, aiming to clarify their connections with ferroptosis and immune regulation.

methodshe 'LIMMA' package in R was used to identify differentially expressed genes (DEGs) in the human heat stress dataset GSE90763. These DEGs were then compared with an established ferroptosis-related gene database and further screened using Cytoscape to identify candidate genes. The levels of ferroptosis-related markers (GSH, MDA, Fe²⁺, GPX4 enzyme activity) and expression patterns of candidate genes were subsequently validated at both transcriptional (qRT-PCR) and protein (ELISA) levels in peripheral blood mononuclear cells from both healthy controls and heat stroke patients. Additionally, Cytoscape and CIBERSORT were employed to analyze the associations between candidate genes, immune response, and ferroptosis.

resultsThe expression of four ferroptosis-related candidate genes, Jun Proto-Oncogene (JUN), Hypoxia-Inducible Factor 1 Alpha (HIF1A), Signal Transducer and Activator of Transcription 3 (STAT3), and Epidermal Growth Factor Receptor (EGFR), was altered in patients with heat stroke and was significantly correlated with elevated mRNA expression of T-cell lineage markers (CD4 and CD8A) in heat stroke patients. Multi-level experimental validation-including GSH depletion, MDA elevation, iron overload, reduced GPX4 enzyme activity, and coordinated protein-level dysregulation of GPX4/SLC7A11/ACSL4-provided strong biochemical evidence suggestive of ferroptosis activation in the peripheral blood of heat stroke patients.

conclusionsIn heat stroke patients, differential expression of the genes JUN, HIF1A, STAT3, and EGFR is associated with increased levels of ferroptosis, and both show a potential association with immune regulation involving elevated T cell activity. These correlative findings generate testable hypotheses and identify candidate biomarkers that warrant further investigation in larger, independent cohorts.