Metabolic reprogramming modulates cardiomyocyte hypertrophy via GLS1 in chronic kidney disease in male mice

Left ventricular hypertrophy (LVH) is a major cardiovascular complication of chronic kidney disease (CKD), yet its mechanisms remain poorly understood. Here we show that in preclinical experiments, CKD drives cardiomyocyte metabolic reprogramming characterized by enhanced glutaminolysis and impaired oxidative phosphorylation in male C57BL/6J mice. Integrated transcriptomic and metabolomic analyses identified early upregulation and activation of glutaminase 1 (GLS1) in CKD hearts, while serum-induced GLS1 activity was associated with LV hypertrophic remodeling in a multicenter peritoneal dialysis cohort. Human myocardial samples also showed increased GLS1 expression in CKD. Cardiomyocyte-specific deletion or pharmacological inhibition of GLS1 attenuated CKD-induced hypertrophy in these mouse models. Proteomic and mechanistic analyses further identified phosphate as a major regulator of GLS1 activity and expression. Excessive GLS1 activation increased ammonia production, disrupted mitochondrial respiratory protein expression and redox homeostasis, and reduced bioenergetic efficiency. These findings identify a phosphate–GLS1–glutaminolysis axis linking the uremic milieu to mitochondrial dysfunction and cardiac hypertrophy, and suggest GLS1 as a potential therapeutic target for CKD-associated LVH. Chronic kidney disease often causes heart enlargement, a serious complication whose mechanisms remain unclear. Here, the authors show that excess phosphate activates the metabolic enzyme GLS1, promoting heart enlargement, while blocking GLS1 protects against this effect in male mice.