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

Article

作者: Zhao, Kun ; Fu, Huazhou ; Hong, Dandan ; Zhu, Rongrong ; Wang, Tianhao ; Zhang, Tao ; Xu, Xining ; Zhou, Yang ; Zhou, Xizhen ; Chi, Jingyun

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.

2026-03-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Corrigendum to “Evaluation of the hepatoprotective effects and pharmacokinetics of pedunculoside in vitro and in vivo” [Eur. J. Pharmacol. 1008 (2025) 178359]

作者: Chen, Xinxin ; Liu, Zhenjie ; Ming-Yuen Lee, Simon ; Pak-Heng Leung, George ; Yuan, Renyikun ; Qiu, Haixin ; Wang, Zheng-Tao ; Gao, Hongwei ; Seto, Sai-Wang ; Yang, Shilin ; Li, Jingjing

2026-02-01·CYTOTECHNOLOGY

Pedunculoside attenuates the progression of neuropathic pain by affecting microglial polarization through Inhibition of the TLR4-NF-κB pathway

Article

作者: Ma, Linwei ; Li, Yuhong ; Guo, Shaohui ; Li, Bingqing ; Huang, Changjun

Neuropathic pain (NP) is a common and disabling condition characterized by microglial polarization-evoked neuroinflammation. Pedunculoside has been implicated in several inflammation-related diseases and exerts the neuroprotective effects However, its role in NP remains unclear. In this study, pedunculoside dose-dependently suppressed LPS-induced activation of BV2 microglial cells by reducing expression of the microglial marker IBA-1, but without obvious cytotoxicity. Immunofluorescence assay further confirmed that pedunculoside decreased % of CD32⁺ M1 microglia and increased % of CD206⁺ M2 microglia in LPS-stimulated microglia, accompanied by reduced expression of M1 microglial marker CD32 and iNOS and increased expression of M2-like microglial marker CD206 and Arg-1, indicating that pedunculoside could reverse LPS-induced microglial polarization from M1 phenotype towards M2 phenotype. Moreover, pedunculoside also attenuated inflammatory response in LPS-treated microglia by lowering pro-inflammatory cytokine levels (IL-1β, TNF-α, and IL-4) and increasing anti-inflammatory IL-10 levels. Mechanistically, the activation of the TLR4-NF-κB pathway in LPS-treated microglia was suppressed by pedunculoside. Furthermore, reactivating this signaling by TLR4 overexpression abrogated pedunculoside-mediated effects on microglial polarization towards M2 and inflammation. In vivo, administration of pedunculoside alleviated pain sensitivity and modulated microglial polarization from M1 to M2 in chronic constrictive injury (CCI)-induced NP mice. Additionally, pedunculoside also alleviated neuroinflammation and suppressed activation of the TLR4-NF-κB pathway in NP mice. Collectively, these findings indicate that pedunculoside may ameliorate the progression of NP by affecting microglial polarization from M1 towards M2 phenotype through inhibition of the TLR4-NF-κB pathway, supporting its potential as a promising therapeutic agent for NP.

100 项与 Pedunculoside 相关的药物交易

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