Abstract

Sepsis-associated myocardial injury is a life-threatening condition, yet its underlying molecular mechanisms remain poorly understood. This study investigates the pathophysiological roles of the stress-responsive transcription factor CCAAT/enhancer-binding protein delta (CEBPD) and matrix metalloproteinase-8 (MMP8), hypothesizing that they constitute a key signaling axis in septic cardiomyopathy. An in vitro sepsis model was established using primary neonatal rat cardiomyocytes (NRCMs), which were exposed to serum derived from validated animal models of sepsis/septic shock and corresponding controls to mimic the clinical microenvironment. Gene expression, cell viability, apoptosis, and inflammatory responses were assessed using a range of molecular and cellular biology approaches. Direct regulatory interactions were verified through dual-luciferase reporter and chromatin immunoprecipitation assays, while functional relevance was further confirmed via rescue experiments. CEBPD expression was significantly elevated in the serum of endotoxin shock animals as well as in serum-stimulated NRCMs. Moreover, CEBPD overexpression promoted cardiomyocyte apoptosis and inflammation, whereas its silencing conferred protection by attenuating cellular injury and inflammatory activity. Mechanistically, CEBPD was shown to directly transactivate MMP8. Notably, MMP8 knockdown reproduced the protective effects against apoptosis observed following CEBPD suppression. Conversely, enforced MMP8 expression completely reversed the anti-apoptotic and anti-inflammatory effects of CEBPD knockdown, identifying MMP8 as a critical downstream mediator of CEBPD-driven pathogenicity. These findings delineate a potential mechanism underlying septic cardiomyopathy mediated through the CEBPD–MMP8 signaling pathway. Septic stress induces CEBPD upregulation, which directly activates MMP8 expression, thereby triggering cardiomyocyte apoptosis and inflammation. This newly characterized axis highlights a mec