Abstract

Doxorubicin-induced cardiomyopathy (DiCM) involves impaired clearance of apoptotic cardiomyocytes (efferocytosis) by cardiac macrophages. This study reveals a central role for the MARCH2-NR1H2 axis in this process. We find that MARCH2 expression is significantly reduced in cardiac macrophages from DiCM mice and human dilated cardiomyopathy patients. Genetic ablation of MARCH2, either globally (MARCH2−/−) or specifically in resident cardiac macrophages (MARCH2f/f; CX3CR1Cre), exacerbates DiCM, impairs efferocytosis, and increases inflammation. Mechanistically, MARCH2 enhances the protein stability of the nuclear receptor NR1H2 via K27-linked polyubiquitination, leading to upregulation of the efferocytosis receptor MERTK. Conversely, macrophage-specific NR1H2 deficiency (NR1H2f/f; CX3CR1Cre) suppresses efferocytosis and worsens cardiac dysfunction. Importantly, pharmacological activation of NR1H2 attenuates DiCM progression. These findings identify the MARCH2-NR1H2 axis as a key regulator of macrophage efferocytosis and a potential therapeutic target for DiCM. Doxorubicin-induced cardiomyopathy involves impaired clearance of dead cardiomyocyte by cardiac macrophages, which exacerbates heart damage. Here, the authors show that enhancing the MARCH2- NR1H2 pathway improves this cleanup process and may represent a new treatment strategy.