MARCH2 in cardiac resident macrophages protects against doxorubicin-induced cardiomyopathy by stabilizing NR1H2 through K27-linked polyubiquitination, thereby enhancing apoptotic cardiomyocyte clearance.
Does modulation of the MARCH2-NR1H2 axis or pharmacological activation of NR1H2 prevent doxorubicin-induced cardiomyopathy in preclinical models?
The MARCH2-NR1H2 axis is a key regulator of macrophage efferocytosis and represents a potential therapeutic target for preventing doxorubicin-induced cardiomyopathy.
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.
Published April 10 2026 with rapid 1,863 accesses in first days. High novelty in cardio-oncology efferocytosis pathway generating expert commentary on X and ResearchGate (~45 cardiology threads). Potential practice disruption for chemotherapy patients. Discussed in Nature Reviews Cardiology ecosystem and Chinese cardiology networks.
Liu et al. (Fri,) conducted a other in Doxorubicin-induced cardiomyopathy. MARCH2 genetic ablation vs. Wild-type was evaluated on Cardiac function and efferocytosis. MARCH2 in cardiac resident macrophages protects against doxorubicin-induced cardiomyopathy by stabilizing NR1H2 through K27-linked polyubiquitination, thereby enhancing apoptotic cardiomyocyte clearance.