TM9SF1 aggravates liver ischemia-reperfusion injury by promoting autophagy

Liver transplantation (LT) stands as the sole effective approach for addressing end-stage liver disease. Autophagy plays an indispensable role in liver ischemia-reperfusion（I/R）. Transmembrane 9 superfamily member 1 (TM9SF1) is a transmembrane protein that has been shown to be associated with autophagy. However, the role and mechanism of this protein in liver I/R injury have not been explored. We found that TM9SF1 expression increased in liver I/R injury mice and AML12 cells after hypoxia-reoxygenation (H/R). Then, we constructed TM9SF1 adeno-associated virus overexpression and knockdown (KD) mice and constructed a liver I/R injury model. The results showed that TM9SF1-overexpressing mice had increased liver damage, inflammation, and autophagy levels. The opposite changes were observed in knockdown mice. Mechanistically, we found that TM9SF1 and Annexin A2 (ANXA2) interacted and jointly affected the expression of autophagy levels during liver I/R injury. Based on the construction of TM9SF1-overexpressing mice , we interfered with the expression of ANXA2 and found that the degree of liver damage was reduced, the level of inflammation decreased, and the level of autophagy decreased. Finally, we performed virtual screening on the FDA-approved molecular library and found that lomitapide can reduce the expression of TM9SF1, thereby alleviating liver ischemia-reperfusion injury. In general, our findings indicated that TM9SF1 and ANXA2 interact with each other, affecting autophagy levels through the mitogen-activated protein kinase (MAPK) pathway, thereby aggravating liver I/R injury. Targeting TM9SF1-ANXA2 may be a potential therapeutic strategy.