Loss of RhoA in microglia disables glycolytic adaptation and impairs spinal cord injury recovery through Arhgap25/HIF-1α pathway.

RhoA, a small GTPase, plays a pivotal role in various diseases, including spinal cord injury (SCI). Although RhoA inhibition has been traditionally viewed as beneficial for SCI repair, recent clinical trials of RhoA inhibitors in SCI have failed to show significant therapeutic efficacy, suggesting functional heterogeneity across different cell types. The role of RhoA in microglia, the key immune cells involve in SCI, remains poorly understood. Using microglial RhoA conditional knockout mice, this study demonstrated that RhoA deficiency in microglia attenuates the morphological and functional repair of the SCI mice, and impairs the microglial biofunctions of proliferation, phagocytosis, and migration. Single-cell RNA sequencing, bulk RNA sequencing, and metabolomics revealed that RhoA deficiency can attenuate the microglial glycolytic enzyme expression, ATP production, ECAR and OCR levels through the Arhgap25/HIF-1α pathway. Overall, this is the first study to demonstrate that microglial RhoA is essential for SCI repair, the Arhgap25/HIF-1α pathway mediated glucose metabolism might enlighten a novel insight to enrich the understanding on the complex roles of RhoA and microglia in SCI repair. Moreover, this study highlights the importance of considering cell-specific roles of RhoA in SCI repair and provides a foundation for developing targeted therapies aimed at microglial metabolic reprogramming. Schematic representation of the proposed mechanism by which microglial RhoA regulates glycolytic adaptation and spinal cord repair. (Created by Figdraw.com with permission of # wgq=r7c74c).