Activation of GLP-1R ameliorates microglial pyroptosis after spinal cord injury by restoring FANCC expression.

Abstract

Secondary spinal cord injury (SCI) involves neuroinflammatory mechanisms such as microglial pyroptosis, which aggravates neural impairment via NLRP3 inflammasome activation. Although liraglutide (Lr) is commonly used for managing blood glucose, it also exhibits anti-inflammatory effects. Previous studies from our group have shown that glucagon-like peptide-1 receptor (GLP-1R) activation in microglia attenuates neuroinflammation and promotes functional recovery after SCI, the precise mechanism linking GLP-1R to the inhibition of pyroptosis remained unclear. Here, we report that high-dose Lr (independent of its metabolic effects) significantly improves functional and histological outcomes in a murine SCI model, and these benefits are abolished in GLP-1Rmice. In vitro, RNA sequencing, combined with pharmacological and genetic approaches, revealed that Lr, via the PI3K/Akt/transcription factor EB (TFEB) axis, by upregulates Fanconi anemia complementation group C (FANCC) to suppress pyroptosis. Crucially, FANCC knockdown both elevated p38 phosphorylation and blocked the anti-pyroptotic effect of Lr, thereby establishing FANCC as an essential downstream mediator. This signaling cascade culminates in the inhibition of p38-dependent NLRP3 inflammasome activation. Collectively, our work defines a novel GLP-1R/PI3K/Akt/TFEB/FANCC/p38 pathway through which Lr alleviates secondary SCI, identifying FANCC as a pivotal neuroprotective node and supporting the translational potential of GLP-1R modulation in SCI.