Yiqi Huoxue formula attenuates pressure overload-induced chronic heart failure with insomnia via regulation of RORα-mediated mitochondrial fuction.

Yiqi Huoxue (YQHX) formula is an empirical prescription for the treatment of qi deficiency and blood stasis syndrome in traditional Chinese medicine (TCM). Qi deficiency and blood stasis is one of the typical TCM syndromes in heart failure. However, little is known about the mechanism of the YQHX formula in treating heart failure patients with qi deficiency and blood stasis syndrome. This study aimed to systematically investigate the therapeutic mechanisms of YQHX formula in heart failure with comorbid insomnia. HPLC-Q-TOF-MS/MS analysis identified twenty-one bioactive components in the YQHX formula, including caffeic acid, hydroxysafflor yellow A, and salvianolic acid B. Research results in vivo revealed that treatment with YQHX formula significantly improved cardiac function and alleviated myocardial injury in the mice model of TAC-induced HF. Meanwhile, YQHX formula effectively suppressed pressure overload-induced cardiac hypertrophy and significantly ameliorated insomnia and anxiety-like behaviors through modulation of neurotransmitter systems. Mechanistically, YQHX formula upregulated RORα expression, thereby facilitating mitophagy and restoring mitochondrial dynamics homeostasis. Consistent with these in vivo findings, in vitro experiments demonstrated that YQHX formula markedly inhibited Ang II-induced cardiomyocyte hypertrophy, enhanced mitochondrial membrane potential (ΔΨm), reduced reactive oxygen species (ROS) production and preserved mitochondrial structural integrity. Our findings identify the promotion of the RORα pathway as the underlying mechanism through which the YQHX formula alleviates heart failure and comorbid insomnia, offering new insights into the prevention and treatment of cardiovascular diseases accompanied by sleep disturbances.