Heart failure (HF) is a complex clinical syndrome that represents the end result of several pathophysiologic processes. Despite a dramatic evolution in diagnosis and management of HF, most patients eventually become resistant to therapy. Xin-Li Formula (XLF) is a Chinese medicine formula which shows great potential in the treatment of HF according to our previous studies. The present study was designed to investigate the effects of XLF on HF induced by a combination of hyperlipidemia and myocardial infarction (MI) in rats and reveal the underlying mechanism.A rat model of HF induced by hyperlipidemia and MI was established with intragastric administration of XLF and Perindopril. In vitro, CD4+ T cells from mouse spleen and LPS/ATP-stimulated THP-1 macrophages were employed.XLF was shown to have markedly protective effects on MI-induced HF with hyperlipidemia in rats, including improvement of left ventricular function, reduction of left ventricular fibrosis and infarct size. Moreover, XLF administration significantly increased the number of Foxp3+ Tregs, and inhibited mTOR phosphorylation and NLRP3 signaling pathway. In vitro, we found that XLF had induced Treg activation via the inhibition of mTOR phosphorylation in CD4+ T cells. Additionally, XLF inhibited NLRP3 inflammasome activation in LPS/ATP-stimulated THP-1 macrophages. Taken together, this study raises the exciting possibility that Xin-Li Formula may benefit HF patients due to its immunomodulatory and anti-inflammatory effects via Treg activation and NLRP3 inflammasome inhibition.© 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.