Screening and Clinical Validation of Ferroptosis‐Related Genes in Acute Ischemic Stroke

ABSTRACT Background Ferroptosis is strongly implicated in IS‐induced neurodegeneration, so it is critical to identify therapeutic targets within this cell death pathway. Methods The Gene Expression Omnibus (GEO) microarray dataset GSE58294 was screened for genes differentially expressed between AIS patients and controls, and the resulting gene set intersected with the FerrDb database to identify genes also related to ferroptosis. Genes strongly linked to AIS and ferroptosis were further selected by protein–protein interaction (PPI) network analysis. Strong candidates were validated in a second GEO dataset and another AIS patient cohort. Results Six key genes, including HMOX1 and STAT3, were significantly upregulated in AIS and demonstrated diagnostic value. The protein–protein interaction network analysis revealed that HMOX1 and STAT3 occupied central hub positions with direct interaction. Clinical validation using multivariable logistic regression confirmed that elevated serum levels of HMOX1, STAT3, and pSTAT3 (OR > 1), along with decreased GPX4 (OR < 1), are independent indicators for distinguishing cerebral infarction patients from healthy controls (all p < 0.05). Furthermore, these protein levels were also positively correlated with both infarct volume and NIHSS scores. The biomarker panel that was comprised of HMOX1, pSTAT3 achieved an AUC of 0.774 in detection, significantly outperforming individual markers. Conclusion We posit that HMOX1 synergizes with STAT3 to inhibit GPX4 expression and promote ferroptosis. These genes may be effective prognostic biomarkers and therapeutic targets for AIS.