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

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.