Oxidative Stress and Pyroptosis Mediated by CEBPB/HMGB1 Signaling in Sepsis-Exacerbated Coronary Atherosclerosis

Aims: This study explores the role of oxidative stress and the CEBPB/HMGB1/VCAM1 signaling axis in sepsis-exacerbated coronary artery disease (CAD). Methods: A sepsis-exacerbated CAD model was established in male ApoE^-/- mice using cecal ligation and puncture (CLP) surgery followed by a high-fat diet (HFD) to induce coronary atherosclerosis. Lentiviral-mediated overexpression and knockdown of CEBPB and VCAM1 were performed via tail vein injection. In vitro experiments employed THP-1-derived macrophages and human aortic endothelial cells (HAECs). Key methodologies included single-cell RNA sequencing, bulk transcriptomics, chromatin immunoprecipitation, dual-luciferase reporter assays, enzyme-linked immunosorbent assay, reactive oxygen species (ROS) detection, and flow cytometry to elucidate the molecular mechanisms of the CEBPB/HMGB1/VCAM1 axis. Results: CEBPB was upregulated in macrophages under septic conditions, promoting HMGB1 transcription and triggering pyroptosis and ROS overproduction. Released HMGB1 enhanced macrophage-endothelial adhesion and upregulated VCAM1 expression in endothelial cells (ECs) via the NF-κB pathway, contributing to endothelial dysfunction. These effects were validated in vivo using the CLP + HFD mouse model, where CEBPB knockdown or VCAM1 overexpression modulated inflammatory and vascular markers. In vitro, functional damage to ECs was observed upon co-culture with activated macrophages, but this was alleviated by targeting HMGB1 or VCAM1. Innovation: The CEBPB/HMGB1/VCAM1 axis links systemic inflammation to oxidative vascular damage in sepsis, offering a therapeutic target for CAD complications. Conclusion: The findings provide novel insights into the interplay of oxidative stress and inflammatory signaling in sepsis-exacerbated CAD, suggesting actionable strategies to prevent cardiovascular complications. Antioxid. Redox Signal. 43, 886-912.