Nuclear factor erythroid 2-related factor 2 gene expression in patients with heat stroke and its association with...

Heat strokes represent a critical health issue with high mortality when severe, yet treatments are limited and do not target core pathogenic mechanisms. Oxidative stress is instrumental in heat stroke progression and is closely related to inflammatory activation and endothelial damage. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key antioxidant signaling molecule in sepsis, ischemia-hypoxic encephalopathy, and trauma, although its potential role(s) in heat stroke is unknown.

From January 2023 to June 2025, we enrolled patients with heat stroke and healthy volunteers at the General Hospital of the Southern Theater Command of the Chinese People's Liberation Army. Participants were divided into mild/severe heat stroke and control groups. Data collection included demographic characteristics, vital signs, disease-severity scores (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment [SOFA]), laboratory parameters (creatinine, total bilirubin, white blood cell count, procalcitonin, C-reactive protein, D-dimer, creatine kinase, prothrombin time, and platelet counts), and outcome measures (length of hospitalization and mortality).

We enrolled 49 patients with heat stroke (34 mild cases and 15 severe cases). Mortality did not differ between groups, but hospital stays were significantly longer in the severe group (11 days [range, 9-56]). Disease severity was greater in severe cases (APACHE II: 20 [13-24], SOFA: 10 [6-14]; p < 0.0001). Inflammation and organ-dysfunction markers were significantly higher in severe heat stroke group. Transcriptomic analysis showed that NRF2 and its downstream gene NAD(P)H quinone oxidoreductase 1 (NQO1) were expressed at significantly lower levels in patients with severe heat stroke compared than in healthy controls and mild cases. Blood malondialdehyde, advanced protein oxidation product, protein carbonyl, 8-hydroxydeoxyguanosine, and interleukin-6 levels in patients with severe heat stroke were significantly elevated. Correlation analysis showed that NRF2 expression correlated significantly with disease severity.

Patients with severe heat stroke demonstrated more extensive organ damage, oxidative stress, and inflammatory injury than those with mild heat stroke and healthy controls. Early after severe heat stroke, NRF2 and its downstream antioxidants HO-1 and NQO1 were significantly downregulated, suggesting that impaired NRF2-mediated antioxidant defense promotes disease pathogenesis.