FGF4 activates FGFR1 - PI3K/AKT signaling to enhance Clec10a-mediated intracellular myelin debris processing and promote spinal cord repair

UNLABELLED: Myelin debris accumulation after spinal cord injury (SCI) drives persistent neuroinflammation, lysosomal dysfunction, and lipid overload in macrophages, ultimately impairing tissue repair. Here, we identify fibroblast growth factor 4 (FGF4) as a previously unrecognized regulator of macrophage-mediated myelin debris clearance. Endogenous FGF4 transiently increased in the early phase of SCI but rapidly declined. Using in vitro models, we demonstrate that exogenous FGF4 markedly enhances myelin debris phagocytosis through activation of the FGFR1-PI3K/AKT signaling pathway, leading to upregulation of Clec10a, a C-type lectin receptor not previously linked to myelin debris processing. Silencing Clec10a significantly mitigated the phagocytic and neuroprotective benefits of FGF4, supporting Clec10a as an important mediator of this response. D-GalNAc competitive inhibition assays showed that Clec10a does not rely on the conserved carbohydrate-recognition domain to bind to myelin debris. FGF4 enhanced the maturation and degradative efficiency of the endolysosomal system, driving internalized myelin debris through Rab5+ early endosomes, Rab7+ late endosomes, and Lamp1+ lysosomes, where CTSD-mediated proteolysis was restored. This correction of lysosomal dysfunction was accompanied by reduced lysosomal membrane permeabilization. In vivo administration of FGF4 enhanced myelin debris clearance and alleviated lipid accumulation at the injury site, accompanied by attenuation of NLRP3 inflammasome activity and a shift in macrophage phenotypes toward a reparative state. Together, our results identify FGF4 as a previously unrecognized regulator of macrophage phagosome maturation and lysosomal function after spinal cord injury, linking FGFR1–PI3K/AKT signaling to Clec10a-mediated intracellular processing of internalized myelin debris and inflammation resolution.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03743-0.