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.