2. Academic Validation
  3. Schisandrin B alleviates liver allograft rejection by stabilizing ACOD1 in Kupffer cells to potentiate itaconate-NRF2-mediated suppression of CD8+ T cell chemotaxis

Schisandrin B alleviates liver allograft rejection by stabilizing ACOD1 in Kupffer cells to potentiate itaconate-NRF2-mediated suppression of CD8+ T cell chemotaxis

  • Phytomedicine. 2026 May:154:158031. doi: 10.1016/j.phymed.2026.158031.
Yihua Wang 1,  Dadi Peng 2,  Dengliang Lei 2,  Liqing Jiang 3,  Song Xiang 4,  Qiuying Li 2,  Hong Zhang 5,  Zhongjun Wu 6,  Chao Yu 7,  Tengxiang Chen 8
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou, China; Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550009, Guizhou, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550009, Guizhou, China.
  • 2 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 3 Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 4 Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 5 Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou, China.
  • 6 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
  • 7 Department of Hepatobiliary Surgery, the Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou, China. Electronic address: [email protected].
  • 8 Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550009, Guizhou, China; Guizhou Institute of Precision Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang 550009, Guizhou, China; Engineering Research Center of Chronic Disease Diagnosis and Treatment, School of Basic Medicine, Guizhou Medical University, Guiyang 550009, Guizhou, China. Electronic address: [email protected].
PMID: 41795300 DOI: 10.1016/j.phymed.2026.158031
Abstract

Introduction: Preventing acute rejection is critical for achieving durable survival following liver transplantation. Current immunosuppressants are restricted by toxicity and breakthrough rejection, underscoring the urgent need for new treatment approaches.

Objectives: The present study sought to evaluate the therapeutic potential of Schisandrin B (SchB) in attenuating liver allograft rejection.

Methods: An allogeneic orthotopic liver transplantation rat model (Lewis-to-BN) was employed. The effects of SchB were evaluated through functional, histological, and biochemical assessments. Mechanistic insights were obtained from multi-omics analysis, Molecular Biology approaches, and in vitro experiments, including a primary Kupffer cell (KC)-T cell co-culture system.

Results: SchB treatment significantly prolongs allograft survival, attenuates liver injury, and reduces CD8⁺ T cell infiltration. Multi-omics analysis and functional assays reveal that SchB markedly upregulates the immunometabolite itaconate in KCs. KC-specific knockdown of Acod1, the key enzyme for itaconate synthesis, abolishes the protection of SchB, which is restored upon supplementation with the itaconate derivative 4-OI. Mechanistically, SchB directly bound to ACOD1, disrupting its interaction with NEDD4, a newly identified E3 ubiquitin Ligase for ACOD1, thereby inhibiting K48-linked ubiquitination and subsequent proteasomal degradation. Accumulated itaconate activates NRF2, which alleviates oxidative stress and suppresses the expression of T-cell chemoattractant CXCL10, ultimately reducing CD8⁺ T cell recruitment.

Conclusions: this study unveils a novel mechanism by which SchB stabilizes ACOD1 in KCs to enhance itaconate-NRF2 signaling, suppressing CXCL10-mediated CD8⁺ T cell chemotaxis and alleviating rejection, positioning SchB as a promising immunometabolic agent for liver allograft rejection.

Keywords

Itaconate; Kupffer cell; Liver allograft rejection; Schisandrin B; T cell chemotaxis.

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