TM9SF1 Aggravates Liver Ischemia–Reperfusion Injury by Promoting Autophagy

Liver transplantation (LT) remains the only effective treatment for end-stage liver disease. Autophagy critically regulates liver ischemia–reperfusion (I/R) injury. Transmembrane 9 superfamily member 1 (TM9SF1) is a transmembrane protein associated with the elevation of autophagy. However, the role and mechanism of this protein in liver I/R injury have not been explored. We observed upregulated TM9SF1 expression in liver I/R mice models and AML12 cells subjected to hypoxia-reoxygenation (H/R). Using TM9SF1 adeno-associated virus (AAV) to generate overexpression and knockdown (KD) mice with liver I/R injury, we found that TM9SF1-overexpressing mice exhibited exacerbated liver damage, inflammation, and autophagy, whereas KD-TM9SF1 mice showed opposite results. Mechanistically, we found that TM9SF1 and Annexin A2 (ANXA2) interacted and jointly promoted the expression of autophagy levels during liver I/R injury. Virtual screening of FDA-approved compounds identified lomitapide as an inhibitor that selectively suppresses TM9SF1 expression, thereby attenuating I/R injury. In general, our findings indicated that TM9SF1 and ANXA2 interact with each other, promoting autophagy levels through activating the mitogen-activated protein kinase (MAPK) pathway, thereby aggravating liver I/R injury. Targeting TM9SF1-ANXA2 may be a potential therapeutic strategy.