TMEM87a Maintains Cardiomyocyte Integrity by Limiting Ferroptosis in Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a major cause of heart failure, but the organelle-level mechanisms linking cardiomyocyte stress to maladaptive remodeling remain incompletely defined. Transmembrane protein 87a (TMEM87a) is a Golgi-associated transmembrane protein implicated in organelle homeostasis and ion conductance. Here, we investigated whether TMEM87a regulates cardiomyocyte integrity and DCM pathogenesis. In a doxorubicin-induced mouse model of DCM, cardiac TMEM87a expression was increased, suggesting engagement of this pathway during myocardial stress. Cardiomyocyte-specific Tmem87a knockout mice developed spontaneous DCM-like disease, including impaired systolic function, ventricular dilation, elevated plasma brain natriuretic peptide, myocardial fibrosis, and cardiomyocyte hypertrophy. Quantitative proteomics of knockout hearts identified ferroptosis as the most significantly enriched pathway. Consistent with disrupted iron and redox homeostasis, Tmem87a-null hearts showed increased iron-handling proteins, myocardial iron deposition, elevated hydrogen peroxide and malondialdehyde levels, reduced GPX4, and increased PTGS2. Pharmacological inhibition of ferroptosis with ferrostatin-1 improved cardiac function and attenuated pathological remodeling in Tmem87a knockout mice. These findings identify TMEM87a as a previously unrecognized regulator of cardiomyocyte homeostasis and implicate ferroptosis as an important downstream effector of cardiac injury caused by Tmem87a knockout.