NLRP3 Mediated Kupffer Cell Pyroptosis Aggravated Ischemia-reperfusion Injury After Aging Donor Liver Transplantation Through CD38-NAD+-Sirt1 Dependent Acetylation of ERRα.

Aging donor livers (age≥60 years) are increasingly used in liver transplantation, but remain highly vulnerable to ischemia-reperfusion injury (IRI). Sustained activation of the NLRP3 inflammasome and macrophage pyroptosis are key features of hepatic IRI, yet the upstream mechanism responsible for persistent NLRP3 activation in aging liver macrophages is unclear. Analysis of human liver graft samples revealed the clinical association of CD38-related NAD+ dysregulation with transplantation-associated injury, while mechanistic investigations using mouse models and macrophage systems identified the CD38-NAD+-SIRT1-ERRα-NLRP3 pathway underlying aging-associated IRI. Consistently, aging grafts developed more severe IRI and macrophage pyroptosis than young grafts, whereas conditional deletion of CD38 in Kupffer cells partially alleviated these changes in vivo and in vitro. Mechanistically, CD38-associated NAD+ depletion impaired SIRT1 activity, reduced ERRα deacetylation at lysine 129, and affected ERRα-mediated regulation of NLRP3 transcription. Moreover, a nano-delivery system carrying the CD38 inhibitor 78c effectively reduced Kupffer cell pyroptosis and attenuated IRI in aging donor livers. These findings identify the CD38/NAD+/SIRT1/ERRα/NLRP3 signaling pathway as a potential regulatory axis linking aging-associated metabolic dysfunction with graft susceptibility to IRI.