Taohong Siwu decoction ameliorates hepatic lipid accumulation in female mice with heart failure and preserved ejection fraction via AMPK/SREBP1 pathway

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) theory, both heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated fatty liver disease (MAFLD) are commonly associated with the syndrome of "qi stagnation and blood stasis," which manifests as cardiac dysfunction and hepatic metabolic disturbance, respectively. Taohong Siwu decoction (THSWD), a classic TCM formula documented in Yi Zong Jin Jian for promoting blood circulation and resolving stasis, is therefore a rational candidate to address this shared pathological basis. While THSWD's separate benefits for heart and liver have been reported, its potential to treat the interconnected pathology of HFpEF-associated MAFLD remains unexplored. AIM OF THE STUDY: This study aimed to investigate THSWD's therapeutic potential against HFpEF-associated MAFLD and its molecular mechanisms. MATERIALS AND METHODS: A two-hit HFpEF model was established in female mice. Hepatic lipid accumulation was evaluated by measuring triglyceride content, along with Oil Red O and H&E staining. THSWD constituents were identified by UPLC-Q-ToF/MS, and molecular targets were predicted through network pharmacology integrated with RNA-seq of liver tissues, then validated by qPCR and Western blotting. An in vitro steatotic HepG2 model further evaluated the effects of THSWD on lipid accumulation. RESULTS: THSWD significantly reduced hepatic lipid accumulation in HFpEF mice. UPLC-Q-ToF/MS identified 51 compounds in THSWD. Network pharmacology suggested these compounds target multiple lipid metabolism genes, particularly via the AMPK pathway. RNA-seq confirmed downregulation of key lipogenic SREBP1-regulated lipogenic genes (Acaca, Fasn, Scd1), validated by qPCR and Western blotting. In steatotic HepG2 cells, THSWD reduced lipid accumulation via AMPK/SREBP1 signaling, as this effect was abolished by either AMPK selective inhibitor or AMPKα1/α2 siRNA knockdown. Furthermore, when SREBP1 knockdown was combined with THSWD treatment, no additive effect on lipid reduction was observed compared to THSWD alone, indicating that SREBP1 mediates the lipid-lowering action of THSWD as a key downstream effector. CONCLUSION: This study provides the first evidence that THSWD alleviates HFpEF-associated MAFLD by suppressing lipid biosynthesis through AMPK/SREBP1 signaling, highlighting its potential as a therapeutic strategy for hepatic steatosis in HFpEF.