# Mast Cell‐Derived CXCL4: A Key Mediator of Ferroptosis and Cardiac Damage in Septic Cardiomyopathy

## TL;DR

This study shows that mast cell-derived CXCL4 causes macrophage death and heart damage in septic cardiomyopathy through ferroptosis and a specific signaling pathway.

## Contribution

The novel finding is that CXCL4 from mast cells drives ferroptosis and cardiac injury via the STAT3/P53 pathway in septic cardiomyopathy.

## Key findings

- CXCL4 levels rise in SCM, linked to mast cell activation and macrophage ferroptosis.
- Inhibiting STAT3 or P53 reduces ferroptosis and improves heart function in SCM models.
- CXCL4 impairs macrophage phagocytosis, worsening cardiac damage.

## Abstract

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.

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&E, toluidine blue staining), survival analysis, ELISA, Western blot, immunofluorescence, immunohistochemistry, TUNEL staining, and detection of myocardial markers (CK‐MB, AST, LDH) and oxidative stress indicators (SOD, MDA, iron content). In vitro, RAW264.7 macrophages were treated with CXCL4 alone or combined with inhibitors (Fer‐1, PFT‐α, Niclosamide), followed by CCK‐8 assay, ROS detection, qRT‐PCR, Western blot, and phagocytosis microbead assay.

In vivo, SCM mice exhibited significantly elevated CXCL4 levels in serum and heart tissue, accompanied by mast cell activation and degranulation. Inhibiting mast cell activation (with CS) reduced CXCL4 production, alleviated cardiac inflammation and ferroptosis (increased SLC7A11/GPX4 expression, decreased 4‐HNE), and improved survival. TUNEL staining revealed predominant macrophage death in SCM hearts. In vitro, CXCL4 induced macrophage ferroptosis (downregulated SLC7A11/GPX4) and impaired phagocytic function (reduced CD36/MERTK expression), which was reversed by Fer‐1. Mechanistically, CXCL4 activated STAT3 phosphorylation, regulating downstream P53; inhibiting STAT3 (Niclosamide) or P53 (PFT‐α) alleviated macrophage ferroptosis, restored phagocytosis, and mitigated cardiac injury in SCM mice.

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.