Exploration of SOCS3 and HSPA1A in PANoptosis during acute myocardial infarction and chronic kidney disease.

Introduction: Chronic kidney disease (CKD) is an independent risk factor for acute myocardial infarction (AMI), but the mechanisms underlying their comorbidity remain unclear. As a newly described inflammatory form of programmed cell death, PANoptosis may play a key role. This study aimed to identify shared pathogenic mechanisms and key targets linking the two diseases. Methods: Mendelian randomization analysis was performed to assess the causal relationship between CKD and coronary artery disease (CAD). Shared genes among AMI, CKD, and PANoptosis were identified, followed by functional enrichment analysis. Diagnostic performance of key genes was evaluated using independent cohorts. Single cell sequencing was applied to localize gene expression at the cellular level. In vivo animal experiments were conducted to validate the functional role of the candidate gene SOCS3 in post MI PANoptosis and cardiac function. Results: Mendelian randomization confirmed that CKD is a significant risk factor for CAD. We identified 12 genes shared by AMI, CKD, and PANoptosis, and determined SOCS3 and HSPA1A as key diagnostic genes. Both genes displayed strong diagnostic performance (e.g., AUCs > 0.85 for AMI) in independent cohorts. Functional analysis showed enrichment in pathways including JAK STAT signaling and apoptosis. Single-cell sequencing localized high expression of these genes to monocytes and endothelial cells. Animal experiments demonstrated that knockdown of SOCS3 significantly inhibited expression of key PANoptosis molecules such as CASP1, CXCL10, and ZBP1 after MI, reduced inflammation, and improved cardiac function. Discussion: PANoptosis was the central pathological link connecting CKD and AMI. As shared biomarkers and intervention targets, SOCS3 and HSPA1A provided new directions for precise diagnosis and treatment of cardiorenal comorbidities.