Sirt1-eIF2α axis drives pro-inflammatory macrophage activation through ER stress aggravating liver IRI in aged mice

The critical shortage of donor livers has necessitated the adoption of aged donor organs, despite their increased susceptibility to ischemia-reperfusion injury (IRI) post-transplantation. Our study demonstrates that in aged mice subjected to IRI, hepatic injury exacerbates during the late phase, accompanied by a significant increase in pro-inflammatory polarization of hepatic macrophages. This phenomenon is associated with abnormal elevation of eukaryotic translation initiation factor 2α (eIF2α) acetylation. Further investigation reveals that NAD + levels markedly decline in aged hepatic macrophages following IRI, leading to Sirt1 activity reduction and subsequent impairment of its deacetylase function, thereby promoting eIF2α hyperacetylation. Both in vivo and in vitro experiments show that β-nicotinamide mononucleotide (NMN) supplementation restores Sirt1 activity in aged hepatic macrophages, reduces eIF2α acetylation, alleviates endoplasmic reticulum stress, and suppresses the expression of proinflammatory cytokines (TNF-α, iNOS, and IL-1β), while mitigating pro-inflammatory polarization. These findings suggest that NMN, by modulating macrophage phenotype, holds promise as a therapeutic strategy to improve the viability of marginal liver grafts.