LingGui QiHua-3 decoction (LGQH-3) ameliorates cardiorenal dysfunction in HFpEF by restoring fluid homeostasis via the PCSK6/Corin/p38 MAPK/AQPs axis

LingGui QiHua-3 decoction (LGQH-3) is a clinical formulation for heart failure with preserved ejection fraction (HFpEF) associated with fluid retention. As a derivative of Zhenwu Decoction, it embodies to the ethnopharmacological principles of warming “yang”, promoting “qi” transformation, and draining water to manage cardiorenal fluid dysregulation. However, its pharmacological underlying mechanisms remain unclear. This study aimed to determine whether LGQH-3 protects against HFpEF by restoring cardiorenal fluid metabolism, and to elucidate the underlying molecular mechanisms involved in coordinated cardiac and renal fluid regulation. HFpEF was induced in mice via high-fat diet and L-NAME administration. Mice model were evaluated by echocardiography, exercise tolerance, histopathology, and biochemical assays. Candidate pathways were identified through UHPLC-MS and network pharmacology, and subsequently validated by RT-qPCR, WB, ELISA, and immunohistochemistry. Mechanistic relevance was further examined in AC16 cardiomyocytes and HK-2 renal tubular epithelial cells using pharmacological inhibition. LGQH-3 improved diastolic function and exercise tolerance, attenuated cardiac hypertrophy/fibrosis and renal injury, reduced pulmonary congestion, and increased urine output. Mechanistically, LGQH-3 inhibited pathological p38 MAPK activation and associated normalized the aberrent expression of cardiac AQP4 and renal AQP2. In parallel, it restored the PCSK6/Corin axis and reactivated natriuretic peptide signaling to re-establish fluid homeostasis. The in vitro findings were consist with the in vivo results, and pharmacological inhibition of p38 MAPK further supported the critical role of the PCSK6/Corin-p38 MAPK/AQPs cascade. LGQH-3 alleviates cardiorenal dysfunction in HFpEF by restoring fluid homeostasis through regulation of the PCSK6/Corin-p38 MAPK/AQPs network, providing a pharmacological basis for its traditional application and clinical translational potential. • LingGui QiHua-3 decoction (LGQH-3) significantly ameliorates cardiorenal dysfunction in heart failure with preserved ejection fraction (HFpEF) mice. • LGQH-3 restoring body fluid metabolism is evidenced by relieved tissue edema and increased urine output. • LGQH-3 exerts treatment effects by regulating the PCSK6/Corin/p38 MAPK/AQPs axis. • In vitro experiments further confirmed the protective effects and mechanism.