Sertad1 exacerbates cardiomyocytes ferroptosis in sepsis-induced myocardial injury by inhibiting HIPK2.

Sepsis-induced myocardial injury leads to severe structural and functional damage. Recent evidence underscores ferroptosis as a critical driver of myocardial injury progression, yet upstream regulators remain poorly defined. This study systematically investigates the role of Sertad1 in myocardial injury pathogenesis, with a focus on its interaction with the stress kinase HIPK2 in regulating ferroptosis. Differential expression analysis revealed a time-dependent upregulation of Sertad1 during early myocardial injury. In vitro, Sertad1 knockdown or HIPK2 overexpression in H9c2 and NRVMs cells mitigated LPS-induced ferroptosis, improving cell survival, reducing ROS/MDA/iron levels, increasing GSH, and preserving mitochondrial integrity. Mechanistically, Sertad1 exerted its effects by downregulating HIPK2. In vivo, CLP-induced septic myocardial injury mice exhibited pathological cardiac damage, systolic dysfunction, elevated cTnI, inflammation, and activated ferroptosis (increased iron, decreased GSH/GSSG ratio, reduced GPX4). Sertad1 knockdown reversed these changes, restored cardiac structure and function, and suppressed ferroptosis, and downregulated HIPK2 levels, confirming HIPK2 as a downstream effector. We delineate a novel Sertad1-HIPK2 regulatory axis in septic myocardial injury, wherein Sertad1 promotes ferroptosis and exacerbates cardiac injury by inhibiting HIPK2. These findings position Sertad1 as a promising therapeutic target and propose HIPK2 activation as a potential strategy to ameliorate sepsis-induced cardiac dysfunction.