MARCH2 prevents doxorubicin-induced cardiomyopathy by stabilizing NR1H2 and promoting clearance of apoptotic cardiomyocytes

Nat Commun. 2026 Apr 10. doi: 10.1038/s41467-026-71580-z. Online ahead of print.

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 (MARCH2^f/f; CX3CR1^Cre), 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 (NR1H2^f/f; CX3CR1^Cre) 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.

PMID:41963318 | DOI:10.1038/s41467-026-71580-z