Targeting a key protein reduces injury in steatotic liver transplantation

Background and aims

Steatotic donor livers are highly susceptible to post-transplant dysfunction; however, the underlying mechanisms remain incompletely understood. This study aimed to investigate the role of galectin-3 (LGALS3)-mediated pyroptosis in steatotic liver graft injury and explore its therapeutic potential.

Methods

A mouse model of steatotic liver transplantation was established. Graft tissues were subjected to RNA sequencing to identify key regulators. In vitro, LGALS3 was modulated in steatotic hepatocytes under ischemia/reperfusion stress to assess its impact on the NLRP3 inflammasome and pyroptosis. The regulatory mechanism by which LGALS3 modulates NLRP3 ubiquitination was further examined. Finally, the therapeutic efficacy of LGALS3 inhibition was evaluated in an orthotopic liver transplantation model.

Results

Transcriptomic analysis identified LGALS3 as a key upregulated molecule in steatotic grafts, associated with pyroptosis pathways. In vitro, LGALS3 overexpression enhanced NLRP3 inflammasome activation and pyroptotic cell death, whereas LGALS3 knockdown exerted protective effects. Mechanistically, LGALS3 modulated NLRP3 inflammasome activity by regulating its ubiquitination. In vivo, pharmacological inhibition of LGALS3 significantly improved graft function, reduced histological injury, suppressed pyroptosis, and prolonged recipient survival.

Conclusions

This study systematically demonstrated that LGALS3 promotes inflammasome activation and pyroptosis after steatotic liver transplantation by regulating the ubiquitination of NLRP3, thereby exacerbating graft injury. Targeted inhibition of LGALS3 and its downstream NLRP3 signaling axis significantly improved liver function and survival outcomes in steatotic liver transplantation models. These findings not only expand our understanding of the molecular mechanisms underlying complications in steatotic liver transplantation but also provide a theoretical and experimental basis for developing novel anti-pyroptotic therapies, with substantial scientific and clinical implications for liver transplantation and other I/R-associated liver diseases.