F-box/LRR-repeat protein 12 reorchestrated microglia to inhibit scarring and achieve adult spinal cord injury repair

and hyper-IL-6, which cannot break through dense scar barriers to reconstruct neural circuits. However, methods for eliminating this process remain elusive. Here, we conducted a multiomics analysis of SCI and identified FBXL12 as an effective target for inhibiting scarring, further promoting spontaneous crossing of axons at the epicenter. We identified N6-Methyladenosine (m6A) modification as the predominant mRNA modification in SCI, with Fbxl12 being a major modification target. Furthermore, m6A modification specifically promoted FBXL12 synthesis in activated microglia. The overexpression of FBXL12 in microglia contributed to its homogeneous distribution and maintained a "scar-less healing" phenotype. Remarkably, FBXL12 therapy effectively reduced extracellular matrix deposition and decreased the scar area by ~70%. Importantly, axons grew through the epicenter and reached a length of more than 2.4 mm 56 days post-SCI, significantly improving motor function and reconstructing the neural circuit. Mechanistically, FBXL12 promoted cytoskeletal reorganization and migration in microglia by catalyzing the K63-linked ubiquitylation of Myosin heavy chain 14 (MYH14). Together, our results identify m6A-FBXL12-MYH14 axis as a novel cytoskeletal reorganization pathway in activated microglia and suggest FBXL12 as an effective target for a novel microglia-based approach to facilitate scarless functional recovery in SCI.