Monocyte Chemoattractant Protein‐Induced Protein 1 Targets Hypoxia‐Inducible Factor 1α to Protect Against Hepatic Ischemia/Reperfusion Injury

Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein‐induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte‐specific Mcpip1 gene knockout and transgenic mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration. A mechanistic study revealed that MCPIP1 interacted with and maintained hypoxia‐inducible factor 1α (HIF‐1α) expression by deubiquitinating HIF‐1α. Notably, the HIF‐1α inhibitor reversed the protective effect of MCPIP1, whereas the HIF‐1α activator compensated for the detrimental effect of MCPIP1 deficiency. Thus, we identified the MCPIP1–HIF‐1α axis as a critical pathway that may be a good target for intervention in hepatic I/R injury. (H epatology 2018; 00:000‐000).