Identification of isoliquiritigenin as a promising compound targeting lactate metabolism for heart failure...

Lactate metabolism plays a pivotal role in heart failure (HF) progression by exacerbating cardiac fibrosis and dysfunction. However, a systematic analysis of candidate compounds targeting lactate metabolism in HF has not been conducted. Initial animal experiments demonstrated that sodium lactate supplementation ameliorated cardiac function in transverse aortic constriction (TAC) mice (all P < 0.05), whereas lactate dehydrogenase A (LDHA) inhibition impaired cardiac function in sham-operated controls (all P < 0.05), establishing lactate metabolism as a critical therapeutic target. Through integration of 335 lactate metabolism-related genes from the MSigDB with HF-associated genes from six Gene Expression Omnibus (GEO) datasets and GeneCards, we employed Connectivity Map to screen candidate compounds. ADMETlab toxicity profiling identified isoliquiritigenin as a promising candidate. Mechanistic studies revealed isoliquiritigenin directly binds to glycogen phosphorylase L (PYGL) protein, as validated by molecular docking and dynamics simulations. In vitro experiments demonstrated its enhancement of Pygl protein stability in cardiomyocytes (all P < 0.05). Furthermore, isoliquiritigenin administration significantly increased myocardial Pygl protein expression, elevated cardiac lactate levels, and improved cardiac function in TAC mice (all P < 0.05). In summary, isoliquiritigenin demonstrates therapeutic potential in alleviating HF by targeting lactate metabolism. Mechanistically, it binds to PYGL protein, enhances its stability, and promotes lactate production in cardiomyocytes. Future studies should employ diverse preclinical models, characterize molecular effects of isoliquiritigenin-PYGL binding, and implement clinical trials to determine isoliquiritigenin's mechanisms and clinical utility.