Monocyte-derived macrophage SQSTM1/p62 deficiency impairs liver repair and regeneration

The liver exhibits a supernormal regenerative capacity in response to partial hepatectomy (PHx), which is a common treatment for malignant liver disease. After PHx, a large number of monocyte-derived macrophages infiltrate into the remaining liver tissue and participate in the occurrence and development of liver regeneration. The expression of P62 in hepatic macrophages increases. To explore the specific role and mechanism of macrophage P62 after PHx, we constructed myeloid cell-specific p62 knockout mice (p62 cKO), performed 30 % partial hepatectomy (30 %PH) in p62 cKO and wild-type mice (p62 WT) groups. Comparing multiple parameters including weight change rate, liver damage area and liver transaminase content between the two groups of mice, p62 cKO mice revealed poorer postoperative recovery. Moreover, macrophages in the livers of p62 cKO mice displayed higher levels of Ly6C expression (Ly6C^high) than p62 WT group. Additionally, p62 WT macrophages exhibited CX3CR1 upregulation, contrasting with concurrent Ly6C downregulation after 30 % PH. Macrophage p62 sustains the stability of CX3CR1 mRNA degradation, consequently leading to higher CX3CR1 expression levels in p62 WT mice than p62 cKO mice. P62 in monocyte-derived macrophages influences macrophage phenotype, enables the transition of macrophages from bone marrow and blood to a reparative phenotype within the liver, thereby expedites the recovery process from inflammation and liver damage, offers targeted therapeutic strategies for managing complications after PHx.