Key result
Fibroblast-derived myocilin impairs cardiomyocyte mitochondria and worsens heart failure progression via SLC3A2-dependent redox imbalance.
Why the study?
Although cardiomyocyte mitochondrial dysfunction is a central driver of HF pathogenesis, the upstream molecular regulators that initiate or amplify these defects remain incompletely understood.
Does myocilin drive cardiomyocyte mitochondrial dysfunction and heart failure progression?
Does myocilin drive cardiomyocyte mitochondrial dysfunction and heart failure progression?
Myocilin acts as a fibroblast-derived paracrine factor that drives cardiomyocyte mitochondrial dysfunction, highlighting the myocilin-SLC3A2 pathway as a potential therapeutic target for heart failure.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for myocilin-SLC3A2 inhibition in heart failure; leaves open translation from murine models to clinical outcomes.
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.
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Yu et al. (2026) studied Heart failure (n=70). Myocilin vs. Non-HF controls / Wild-type mice was evaluated on Cardiac function and mitochondrial dysfunction. Fibroblast-derived myocilin drives cardiomyocyte mitochondrial dysfunction and exacerbates heart failure progression via SLC3A2-dependent redox imbalance.
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