ArticleJournal of diabetes investigation2026
LGR6 couples maresin 1 signaling to glycolytic flux and protein lactylation for the rescue of diabetic cardiomyopathy.
Article in Journal of diabetes investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDiabetic cardiomyopathy (DbCM) is driven by metabolic inflexibility and impaired mitochondrial clearance. While the pro-resolving lipid mediator Maresin 1 (MaR1) shows therapeutic promise, its capacity to correct the underlying metabolic-epigenetic disturbances in DbCM remains undefined. MATERIALS: Db/db mice and palmitic acid (PA)-exposed H9c2 cardiomyocytes were treated with MaR1. Cardiac function and structure were assessed by echocardiography and histological analysis. Myocardial oxidative stress, inflammation, and key molecular pathways were evaluated via immunoblotting, qPCR, immunohistochemistry, and transmission electron microscopy. The role of the putative receptor LGR6 was investigated using siRNA-mediated knockdown.
resultsMaR1 improved cardiac diastolic function, attenuated pathological hypertrophy and interstitial fibrosis, and reduced oxidative stress and inflammatory markers in db/db mice. Mechanistically, MaR1 activated AMPK signaling, restoring the expression of crucial enzymes for both fatty acid oxidation (CPT1B) and glycolysis (PFK-1, HK2). This metabolic reprogramming elevated intracellular lactate, which in turn replenished the deficient global protein lysine lactylation (Kla). Concurrently, MaR1 reactivated the PINK1/Parkin pathway, restoring mitophagy-associated signaling. In vitro, exogenous lactate supplementation recapitulated these effects. Importantly, LGR6 silencing abrogated all MaR1-induced benefits, including glycolytic activation, lactylation rescue, and mitophagic recovery.
conclusionMaR1 protects against DbCM by signaling through LGR6 to restore metabolic flexibility, thereby fueling a lactate-dependent lactylation program that is critically associated with the reactivation of mitochondrial quality control via mitophagy. This study unveils a critical metabolic-epigenetic axis as a novel therapeutic target.
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