2. Academic Validation
  3. Chaihu shugan powder ameliorated chronic pancreatitis by reprogramming SMS2-mediated sphingolipid metabolism in M1 macrophages

Chaihu shugan powder ameliorated chronic pancreatitis by reprogramming SMS2-mediated sphingolipid metabolism in M1 macrophages

  • Phytomedicine. 2025 Dec:149:157565. doi: 10.1016/j.phymed.2025.157565.
Xiaoyin Zheng 1,  Yijing Long 2,  Lu Li 3,  Jiawang Li 2,  Yiqin Wang 3,  Hui Meng 2,  Qi Qiu 3,  Jing Chen 2,  Hao Yang 4,  Qing Xia 3,  Chenxia Han 5,  Dan Du 6
Affiliations

Affiliations

  • 1 West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China; Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China.
  • 2 Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China.
  • 3 West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Division of Liver surgery and NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 6 West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, China; Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610213, China. Electronic address: [email protected].
PMID: 41308384 DOI: 10.1016/j.phymed.2025.157565
Abstract

Background: Chronic pancreatitis (CP) lacks targeted therapies. Its pathogenesis involves macrophage polarization-activated pancreatic stellate cells (PSCs), with sphingolipid metabolism playing an emerging role. The traditional formula Chaihu shugan powder (CSP) shows clinical potential for CP treatment.

Purpose: This study aimed to elucidate the role of CSP in CP and to identify the key components and underlying mechanisms involved in macrophage polarization-PSC activation crosstalk.

Study design: We investigated the effects of CSP in vivo and in vitro, identified differentially altered sphingolipids and metabolic Enzymes, and assessed their impact on macrophage polarization and PSC activation, followed by screening for the active components of CSP.

Methods: CP was induced in mice by cerulein injections for four weeks, with CSP treatment given in the final two weeks. Bone marrow-derived macrophages and primary PSCs were isolated for in vitro studies. Underlying targets and mechanisms were explored using targeted sphingolipid analysis, scRNA-seq, flow cytometry and genetic knockdown, while molecular docking and molecular interaction helped identify active CSP components.

Results: CSP significantly attenuated pancreatic fibrosis and M1 macrophage polarization, and restored sphingolipid metabolism in both serum and pancreas. Elevated sphingomyelin (18:1) and sphingomyelin synthase 2 (SMS2) in macrophages were identified as promoting PSC activation. Hesperetin in CSP bound to SMS2, inhibiting M1 macrophage polarization and PSC activation.

Conclusion: CSP ameliorates CP partially through hesperetin-targeted SMS2, reprograms sphingolipid metabolism, and suppresses M1 macrophage-induced PSC activation.

Keywords

Chaihu shugan powder; Chronic pancreatitis; Macrophages; Sphingolipid metabolism; Sphingomyelin synthase 2.

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