Hrd1 alleviates fatty liver ischemia-reperfusion injury by regulating the phenotypic polarization of Kupffer cells.

To address the persistent shortage of donor livers for transplantation, steatotic grafts are increasingly being accepted as marginal allografts. However, fatty liver is highly susceptible to ischemia-reperfusion injury (IRI), leading to high post-transplant graft dysfunction rates, with no effective alleviation methods available to date. Our previous studies indicated that activated Kupffer cells (KCs) undergo M1 proinflammatory polarization to exacerbate fatty liver IRI, yet the underlying molecular circuitry remains largely undefined. In this study, the IRI in fatty liver mice was found to be more pronounced compared to normal mice, with the polarization of KCs towards M1 type playing a crucial role. In fatty liver, degradation of SOD1-SP1 by endoplasmic reticulum-associated degradation (ERAD) led to increased reactive oxygen species (ROS) accumulation in KCs, thereby inhibited the autophagy of KCs. Impaired autophagy promoted M1-type polarization in macrophages and promoted the secretion of more proinflammatory cytokines. Subsequent IRI further exacerbated this process and aggravated liver damage. Further investigation revealed that the key protein Hrd1 in ERAD plays a crucial role in this process. Specific knockout of the Hrd1 gene in KCs can effectively inhibit the degradation of SOD1-SP1 and the accumulation of ROS, restore autophagic function, thereby promoting the polarization of macrophages toward the M2 phenotype, suppressing the M1 phenotype switch, and exerting hepatoprotective effects. Altogether, these data demonstrated that Hrd1 of KCs may be a potential target to reduce fatty liver associated IRI in liver transplantation.