2. Academic Validation
  3. Therapeutic potential of Sheng-Xian-Tang in doxorubicin-induced chronic heart failure by regulation of phenylalanine metabolism disruption

Therapeutic potential of Sheng-Xian-Tang in doxorubicin-induced chronic heart failure by regulation of phenylalanine metabolism disruption

  • Chin Med. 2026 Jan 12;21(1):29. doi: 10.1186/s13020-025-01316-6.
Tao Pang # 1,  Chao Wang # 1 2,  Guangyang Jiao 1 2,  Xiangcheng Fan 3 4,  Doudou Huang 5,  Zhimin Long 6,  Mengqing Xiao 6,  Lianna Sun 7,  Wansheng Chen 8 9 10,  Feng Zhang 11 12
Affiliations

Affiliations

  • 1 Department of Pharmacy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200003, China.
  • 2 The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University, (Tongde Hospital of Zhejiang Province), Hangzhou, 310014, Zhejiang, China.
  • 4 Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, 310014, Zhejiang, China.
  • 5 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6 AB SCEIX, Shanghai, 200050, China.
  • 7 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • 8 Department of Pharmacy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200003, China. [email protected].
  • 9 The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. [email protected].
  • 10 Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University (Second Military Medica University), Shanghai, 200433, China. [email protected].
  • 11 Department of Pharmacy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200003, China. [email protected].
  • 12 Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Naval Medical University (Second Military Medica University), Shanghai, 200433, China. [email protected].
  • # Contributed equally.
PMID: 41527105 DOI: 10.1186/s13020-025-01316-6
Abstract

Background: Sheng-Xian-Tang (SXT), a traditional Chinese medicine, ameliorates doxorubicin (DOX)-induced chronic heart failure (CHF), yet its molecular mechanisms remain elusive.

Objective: To elucidate SXT's cardioprotective mechanisms against DOX-induced CHF.

Methods: In vivo, cardioprotection was evaluated via echocardiography, oxidative stress assays, and histopathology. Integrated metabolomic and 16S rRNA Sequencing identified metabolic disruptions. Serum pharmacochemistry analysis identified hepatic bioactive compounds targeting phenylalanine hydroxylase (PAH). Molecular docking, CETSA, SPR, and enzyme activity assay validated neomangiferin-PAH interactions.

Results: SXT dose-dependently improved DOX-induced cardiac dysfunction in rats. Metabolomic and microbiome analyses confirmed phenylalanine metabolic disorder in the CHF rats. DOX exposure elevated phenylalanine levels in plasma, urine, and heart, reducing hepatic PAH expression and function while inducing ectopic phenylalanine catabolism in the heart. Phenylalanine administration exacerbated the cardiac abnormalities, whereas SXT effectively prevented attenuated DOX-induced cardiac toxicity. CETSA and SPR revealed a strong binding of neomangiferin to PAH, stabilizing its interaction with cofactor BH4 and preventing DOX-induced PAH inhibition.

Conclusions: SXT mitigated DOX-induced CHF through hepatic PAH modulation. Neomangiferin could enhance PAH stability via competitive binding. Targeting PAH-phenylalanine metabolism emerged as a novel therapeutic strategy for DOX-induced cardiac dysfunction.

Keywords

Cardiotoxicity; Doxorubicin; Metabolomics; Microbiome; Phenylalanine hydroxylase; Sheng-Xian-Tang.

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