HIPK2 mediated regulation of ferroptosis and inflammatory signaling in sepsis-induced myocardial injury.

Sepsis-induced myocardial injury (SIMI) is a major contributor to the high mortality of septic shock, yet its underlying mechanisms remain incompletely understood. This study investigated the role of ferroptosis in myocardial damage and inflammatory responses during sepsis, focusing on its regulation by HIPK2 and the NF-κB/STAT3 signaling pathways. Using a cecal ligation and puncture (CLP)-induced sepsis mouse model and lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes, we demonstrated that ferroptosis is a central driver of myocardial injury, evidenced by mitochondrial structural abnormalities, elevated lipid peroxidation, and impaired cardiac function. Ferroptosis inhibition with ferrostatin-1 (Fer-1) significantly improved survival, preserved myocardial ultrastructure, reduced inflammatory cytokine levels, and alleviated oxidative stress. HIPK2 expression was markedly suppressed during sepsis, correlating with enhanced ferroptosis and activation of NF-κB/STAT3 signaling pathway. Overexpression of HIPK2 in vitro mitigated ferroptosis and downregulated NF-κB-p65 and STAT3 phosphorylation, suggesting a dual regulatory role in ferroptosis and inflammation. Furthermore, Fer-1 treatment not only inhibited ferroptosis but also reduced systemic inflammation, highlighting its therapeutic potential in sepsis. These findings establish ferroptosis as a critical mechanism in septic myocardial injury and identify HIPK2 as one of the key regulators, offering new insights into the interplay between ferroptosis and inflammatory signaling. Targeting ferroptosis may represent a promising dual therapeutic strategy to protect cardiac function and modulate systemic inflammation in sepsis.