Pedunculoside ameliorates metabolic dysfunction-associated steatotic liver disease by targeting HNRNPA1 and modulating PPARα signaling pathway to enhance Mitochondrial Fatty Acid β-Oxidation

  • Phytomedicine. 2026 Apr:153:157910. doi: 10.1016/j.phymed.2026.157910.
Yang Zhou  1 ,  Jingyun Chi  1 ,  Xining Xu  2 ,  Rongrong Zhu  1 ,  Tianhao Wang  1 ,  Tao Zhang  3 ,  Dandan Hong  1 ,  Huazhou Fu  4 ,  Xizhen Zhou  5 ,  Kun Zhao  6
Affiliations
  • 1. Jiangsu Province Engineering Research Center of Molecular Target Therapy and Companion Diagnostics in oncology, Pharmacy Department, Suzhou vocational health college, Suzhou, 215009 China.
  • 2. Kaituo Life Technology (Suzhou) Co., Ltd, Suzhou, 215000 China.
  • 3. Jiangsu Province Engineering Research Center of Development and Translation of Key Technologies for Chronic Disease Prevention and Control, Suzhou Vocational Health College, Suzhou 215009, China.
  • 4. Department of traditional Chinese medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006 China.
  • 5. Department of traditional Chinese medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006 China. Electronic address: [email protected].
  • 6. Department of Nuclear Medicine, Shanghai Jiaotong University Affiliated Sixth People's Hospital South Campus, Shanghai, 201499 China. Electronic address: [email protected].
PMID: 41671881 DOI: 10.1016/j.phymed.2026.157910
Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a significant global health challenge, underscoring an urgent need for novel therapeutic agents that offer enhanced efficacy and improved safety. Pedunculoside (PE), a naturally occurring triterpenoid saponin, has demonstrated promising lipid-modulating properties. Nevertheless, its precise mechanisms of action in the context of MASLD remain unclear.

Purpose: To investigate the anti-MASLD effect of PE and uncover its novel mechanism via targeting heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and regulating downstream PPARα pathway.

Method: The therapeutic potential of PE was evaluated both in primary mouse hepatocytes and in vivo using high-fat, high-cholesterol (HFHC) and high-fat diet (HFD) induced MASLD mouse models. A multi-omics and multi-technique approach was applied, including biochemical assays, histopathology, transcriptomic and lipidomic profiling, alongside target-engagement validation via drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), molecular docking, molecular dynamics simulations, and HNRNPA1 knockout models.

Results: PE significantly improved key metabolic and histological features in MASLD models. Mechanistically, PE was found to directly bind HNRNPA1 (a previously unreported target in MASLD therapeutics). This interaction enhanced the mRNA stability of PPARα, leading to activation of fatty acid β-oxidation. Crucially, HNRNPA1 knockout abolished the beneficial effects of PE, confirming the functional necessity of the PE-HNRNPA1-PPARα axis in vivo.

Conclusion: Our study uncovers a novel therapeutic axis in MASLD, in which PE enhances the stability of PPARα mRNA by directly binding to HNRNPA1, and consequently upregulates fatty acid β-oxidation. These findings not only position PE as a promising therapeutic candidate for MASLD but also identify the HNRNPA1-PPARα regulatory pathway as a potential mechanistic target for treating metabolic liver diseases.

Keywords
Heterogeneous nuclear ribonucleoprotein A1; Metabolic dysfunction-associated steatotic liver disease; Pedunculoside; Peroxisome proliferator-activated receptor alpha; fatty acid β-oxidation.
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