The Role of MCPIP1 in Macrophage Polarization and Cardiac Function Post‐Myocardial Infarction

Abstract Macrophages play a critical role in both initiating and resolving inflammation following MI (myocardial infarction). Their polarization is essential for maintaining cardiac function. This study aims to explore the role of MCPIP1(Monocyte chemotactic protein‐induced protein 1) in regulating macrophage polarization and its impact on heart‐spleen interactions during MI recovery. The role of MCPIP1 was investigated using histological staining, RNA sequencing of bone marrow‐derived macrophages, co‐culture experiments, and validated by western blot. Compared to controls, myeloid MCPIP1‐deficient mice had lower survival rates, larger infarction areas, and more severe inflammatory responses after MI. This was due to increased M1 polarization and impaired conversion to the M2 phenotype. Ferroptosis activation in MCPIP1‐deficient macrophages was inhibited by Fer‐1 and PFT‐α, which promoted M2 polarization and fibroblast activation into myofibroblasts. MCPIP1‐deficient MI mice also showed splenomegaly and elevated levels of circulating macrophages, indicating excessive extramedullary hematopoiesis. Splenectomy improved survival rates and reduced infarction size in MCPIP1‐deficient mice. MCPIP1 suppresses the P53/ferroptosis pathway to regulate macrophage polarization and TGF‐β/SMAD3‐mediated fibroblast activation. Its deficiency exacerbates inflammation through abnormal splenic macrophage output, impairing cardiac repair. MCPIP1 is a promising therapeutic target for modulating ferroptosis and heart‐spleen communication to protect cardiac function following MI.