CMTM7 inhibits TLR4 signaling pathway via promoting Rab5 activation and alleviates acute liver injury.

The activation of macrophages mediated by TLR4 is crucial for innate immune responses, while the regulatory mechanisms of TLR4 are still under investigation. This study demonstrates that CMTM7 inhibits TLR4 pathway activation in macrophages and exerts a protective role in acute liver injury (ALI). CMTM7 is highly expressed in monocytes/macrophages, which is downregulated upon LPS stimulation. CMTM7 inhibits LPS/HMGB1-induced activation of the TLR4 pathway in macrophages. Mechanistically, CMTM7 promotes the binding between Rab5 and Gapex5, leading to the generation of GTP-Rab5, which facilitates the internalization and degradation of TLR4, thereby inhibiting TLR4 signaling activation. Utilizing Cmtm7 myeloid conditional knockout mice, we confirmed the protective role of CMTM7 in ALI and highlighted its therapeutic potential through the adoptive transfer of CMTM7-overexpressing macrophages. This study elucidates a novel regulatory mechanism of TLR4 signaling transduction and provides a novel therapeutic strategy for ALI treatment.