A cuproptosis-related gene signature and the protective role of CDKN1A in sepsis-induced acute respiratory distress syndrome

Background Sepsis-induced acute respiratory distress syndrome (ARDS) is associated with high mortality, and reliable molecular biomarkers remain limited. This study aimed to identify candidate cuproptosis-related diagnostic biomarkers and investigate the protective role of CDKN1A. Methods Differentially expressed genes from GSE10474 were intersected with cuproptosis-related genes, followed by functional enrichment, protein–protein interaction analysis, and machine learning using LASSO, random forest, and support vector machine algorithms. The resulting signature was evaluated in GSE32707 and GSE66890. Immune infiltration and single-cell transcriptomic analyses were performed, followed by experimental evaluation of CDKN1A overexpression in LPS-stimulated alveolar epithelial cells. Results An eight-gene signature comprising CDKN1A, MNDA, TREM1, ACP6, APOO, CHPT1, PIAS3, and SNRNP35 was identified. The models achieved AUCs of 0.786–0.886 in the training cohort and 0.654–0.745 in the validation cohorts. Immune analyses revealed dataset-dependent alterations in immune cell populations. CDKN1A overexpression attenuated LPS-induced cytotoxicity, improved cell viability and tight junction protein expression, modulated cuproptosis-related markers, reduced intracellular copper and mitochondrial reactive oxygen species, and preserved mitochondrial membrane potential. Conclusion The eight-gene signature represents a candidate diagnostic tool for sepsis-induced ARDS. CDKN1A overexpression is associated with protection against LPS-induced alveolar epithelial injury and modulation of cuproptosis-related and mitochondrial markers. Further mechanistic and prospective clinical validation is required.