Macrophage STAT3 signaling contributes to a paracrine inflammatory environment associated with ferroptosis-related cardiomyocyte injury, linking inflammatory macrophages to myocardial injury in septic cardiomyopathy.
Ferroptosis-associated transcriptional features in septic cardiomyopathy show marked heterogeneity across cell types.
Inflammatory macrophages showed prominent STAT3-related inflammatory signaling and extensive predicted communication with cardiomyocytes.
Independent mouse and human transcriptomic cohorts revealed context-dependent changes in ferroptosis driver and suppressor programs.
Conditioned medium from LPS-stimulated macrophages induced ferroptosis-related injury in cardiomyocytes.
STAT3 knockdown in macrophages partially attenuated the ferroptosis-related changes in cardiomyocytes, reduced inflammatory responses, and altered Cp expression.
Ferrostatin-1 further alleviated conditioned-medium-induced cardiomyocyte injury.
Consistent ferroptosis-related molecular alterations were observed in an SCM mouse model.
Septic cardiomyopathy is heart dysfunction that can develop during sepsis, a life-threatening response to infection. This study asked how inflammatory immune cells called macrophages might contribute to heart-cell damage involving ferroptosis, an iron-dependent form of cell death driven by damaging fat oxidation. The researchers combined single-cell gene-expression data, independent mouse and human datasets, cell experiments, and a mouse model of the condition. The analyses suggested that inflammatory macrophages show strong STAT3-related inflammatory signaling and are predicted to communicate extensively with heart muscle cells. In the lab, fluid from macrophages stimulated with a bacterial component (LPS) caused heart cells to show injury, fat oxidation, iron buildup, lower GPX4 (a protective protein), and higher ACSL4 (a protein that promotes ferroptosis). Silencing STAT3 in the macrophages partly reduced these effects and lowered inflammation. A ferroptosis inhibitor, Ferrostatin-1, also reduced the damage. Similar molecular changes appeared in septic cardiomyopathy mice. This research suggests that macrophage STAT3 signaling may help create an inflammatory environment that promotes ferroptosis-related heart cell injury during sepsis. The effects of blocking STAT3 were only partial, and much of the evidence comes from cell models and computational predictions, so the findings point to a possible pathway rather than a proven treatment target.
Qiu S, Dai R, Huang X, Zhu W, Zhang W, Feng L, et al.. (2026). Integrated single-cell transcriptomic and experimental analyses identify macrophage-associated STAT3 signaling contributing to ferroptosis-related injury in septic cardiomyopathy.. Molecular biology reports. https://doi.org/10.1007/s11033-026-12795-7