Systems Biology Identifies TARS2 as a Cardiomyocyte Regulator of Mitochondrial Oxidative Stress in Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM), a leading cause of heart failure, is characterized by progressive cardiomyocyte (CM) loss and mitochondrial dysfunction; yet, the molecular drivers of mitochondrial oxidative stress (MitOS) remain unclear. By integrating bulk, single-cell, and spatial transcriptomics with machine learning, we identified threonyl-tRNA synthetase 2 (TARS2) as a CM-enriched regulator of MitOS. TARS2 was consistently up-regulated in human DCM hearts and associated with apoptotic signaling and enhanced macrophage crosstalk. Functional studies demonstrated that TARS2 overexpression disrupted mitochondrial homeostasis, triggered excessive mitochondrial reactive oxygen species, and induced CM apoptosis, whereas genetic inhibition restored mitochondrial function, reduced apoptosis, and improved cardiac performance. These findings uncover TARS2 as a novel regulator of mitochondrial dysfunction and pathological remodeling in DCM, providing both mechanistic insights and therapeutic implications, and establish a systems biology framework for translational discovery of disease targets in cardiovascular medicine.