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

  • J Ethnopharmacol. 2026 Jul 15:366:121642. doi: 10.1016/j.jep.2026.121642.
Wensheng Qi  1 ,  Chang Liu  1 ,  Dengke Li  1 ,  Huihai Yang  2 ,  Yue Li  1 ,  Miao Zhang  3 ,  Dengwen Zhang  4 ,  Martin Ho Yin Yeung  2 ,  Jie Chen  5 ,  Jingjing Li  6 ,  George Pak-Heng Leung  7 ,  Erfei Song  8 ,  Lei Pang  1 ,  Haichun Ma  9 ,  Yin Cai  10
Affiliations
  • 1. Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China.
  • 2. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China.
  • 3. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China; School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region of China.
  • 4. Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangdong, China.
  • 5. Guangdong Province Key Laboratory of Utilization and Conservation of Food and Medicinal Resources in Northern Region, Shaoguan University, Guangdong, China; College of Biology and Agriculture, Shaoguan University, Guangdong, China.
  • 6. Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China.
  • 7. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong Special Administrative Region of China.
  • 8. Institue of Metabolic Science, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangdong, China.
  • 9. Department of Anesthesiology, The First Hospital of Jilin University, Jilin, China. Electronic address: [email protected].
  • 10. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China; Research Centre for Chinese Medicine Innovation, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region of China; The Hong Kong Polytechnic University Shenzhen Research Institute, Guangdong, China. Electronic address: [email protected].
PMID: 41951193 DOI: 10.1016/j.jep.2026.121642
Abstract

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.

Keywords
AMPK; HFpEF; MAFLD; SREBP1; THSWD.
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