ABSTRACT Background Septic cardiomyopathy (SCM) is a common and life‐threatening complication of severe sepsis, with high mortality due to unclear underlying mechanisms. CXCL4, a key pro‐inflammatory factor, is implicated in various heart diseases, while ferroptosis (iron and lipid hydrogen peroxide‐dependent regulated cell death) plays a crucial role in SCM progression. However, the specific crosstalk between CXCL4, ferroptosis, and SCM remains unelucidated. Methods BALB/c mice were randomly divided into six groups (Control, LPS, LPS + Sodium Cromoglycate (CS), LPS + Ferrostatin‐1 (Fer‐1), LPS + Pifithrin‐α (PFT‐α), LPS + Niclosamide) to establish the SCM model via intraperitoneal LPS injection. In vivo experiments included histopathological examination (H inhibiting STAT3 (Niclosamide) or P53 (PFT‐α) alleviated macrophage ferroptosis, restored phagocytosis, and mitigated cardiac injury in SCM mice. Conclusion Mast cell‐derived CXCL4 induces macrophage ferroptosis via the STAT3/P53 signaling pathway, impairs macrophage phagocytic function, and exacerbates myocardial injury in SCM. Targeting mast cell activation, CXCL4 release, or the STAT3/P53‐ferroptosis axis may serve as promising therapeutic strategies for SCM. Clinical trial number: Not applicable.
Wei et al. (Sun,) studied this question.