Integrated analysis and validation of oxidative stress-related genes in renal ischemia-reperfusion injury

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Renal ischemia-reperfusion injury (IRI) is a major driver of acute kidney injury, with oxidative stress acting as a fundamental initiator of downstream pathological cascades including inflammation. Although numerous molecular mediators have been identified, the key stress-responsive genes that govern inflammatory activation in renal IRI remain incompletely understood. This study aimed to identify key oxidative stress-related genes through bioinformatic screening and explore their functional roles in modulating the inflammatory response in renal IRI. Integrating transcriptomic data from the GSE126805 dataset, we identified 29 oxidative stress-related differentially expressed genes. Weighted gene co-expression network analysis revealed that the green gene module was most strongly correlated with renal IRI, containing 14 genes that overlapped with the differentially expressed set. Through Lasso regression and Support Vector Machine Recursive Feature Elimination algorithms, three core genes FOS , FOSB , and GDF15 , were identified. These genes exhibited significantly elevated expression following reperfusion in both the GSE126805 and GSE90861 datasets, showing strong discriminatory capacity for distinguishing pre- and post-reperfusion states (AUC > 0.9). Integrative analysis in murine models confirmed the rapid upregulation of these genes post-injury. Specifically, Fos expression was widespread throughout the kidney, while Fosb and Gdf15 were primarily localized to proximal tubule cells. Furthermore, in vitro experiments demonstrated that silencing these three genes under OGD/R conditions significantly increased interleukin-6 and C-C Motif Chemokine Ligand 2 expression, suggesting a role in limiting excessive inflammatory activation. These findings suggest that FOS , FOSB , and GDF15 are conserved stress-response genes, identified from an oxidative stress-related gene panel, which are upregulated during renal IRI in vivo and associated with limiting excessive inflammatory activation in renal tubular cells under hypoxia-reoxygenation stress. As AP-1 family transcription factors (FOS and FOSB) and a secreted cytokine (GDF15), these gene products appear to act as adaptive regulators of inflammation. Together, these genes represent potential molecular markers of reperfusion-related stress and candidate regulators of inflammation in renal IRI.