Myocilin drives cardiomyocyte mitochondrial dysfunction via SLC3A2-dependent redox imbalance in heart failure

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. A hallmark of HF progression is profound metabolic remodeling accompanied by mitochondrial dysfunction in cardiomyocytes. Impaired mitochondrial oxidative phosphorylation, excessive reactive oxygen species (ROS) production, and disrupted redox homeostasis collectively drive oxidative damage and compromise mitochondrial integrity, ultimately leading to contractile failure, for which no viable strategies currently exist. Although mitochondrial dysfunction is now recognized as a central driver of HF pathogenesis, the upstream molecular regulators that initiate or amplify these defects remain incompletely understood. Here, we identify myocilin as a fibroblast-derived mediator that drives cardiomyocyte mitochondrial dysfunction and ROS production in HF. Myocilin was consistently upregulated in patients with HF and in murine HF models induced by transverse aortic constriction and isoproterenol, and was predominantly expressed in cardiac fibroblasts. In vivo study using male mice showed that myocilin overexpression exacerbated cardiac dysfunction and fibrosis, whereas genetic ablation markedly alleviated pathological remodeling. Using transwell systems and recombinant protein stimulation, we found that fibroblast-derived myocilin impaired mitochondrial function in cardiomyocytes, as evidenced by reduced ATP production, increased ROS, and loss of membrane potential. Mechanistically, myocilin directly interacted with SLC3A2, the heavy chain that pairs with SLC7A11 to form the cystine/glutamate antiporter, on cardiomyocytes and promoted its degradation, thereby impairing cystine uptake. This led to glutathione depletion and redox imbalance, subsequently triggering ferroptosis-associated mitochondrial dysfunction in cardiomyocytes. Collectively, these findings identify a fibroblast-cardiomyocyte signaling axis in which myocilin disrupts cardiomyocyte metabolic homeostasis. Targeting the myocilin-SLC3A2 pathway may represent a potential therapeutic strategy for HF.