FGF13 Deficiency Ameliorates Paclitaxel-Induced Neuropathic Pain by Inhibiting VASH1-Mediated Microtubule Detyrosination to Promote Mitophagy

Mitochondrial damage in dorsal root ganglion (DRG) neurons contributes to the pathogenesis of paclitaxel (PTX)-induced peripheral neuropathic pain (PIPNP). Fibroblast Growth Factor 13 (FGF13), abundantly expressed in DRG neurons, is crucial for the regulation of somatosensation; however, its role in PIPNP remains unclear. Here, we demonstrated that FGF13 expression is upregulated in DRG neurons of PIPNP model mice. Conditional knockout of Fgf13 in DRG neurons effectively alleviates PTX-induced mitochondrial damage and neuropathic pain. RNA Sequencing analysis revealed that Mitophagy mediates the regulatory effects of FGF13 in PIPNP. Mechanistically, FGF13 physically interacts with vasohibin 1 (VASH1), regulating the binding of VASH1 to microtubules and promoting microtubule detyrosination. FGF13 ablation disrupts assembly of the FGF13-VASH1-α-tubulin ternary complex, impairing VASH1-mediated microtubule detyrosination and increasing microtubule tyrosination. The resulting accumulation of tyrosinated microtubules facilitates kinesin-3 (KIF1A)-driven lysosomal trafficking, which in turn promotes Mitophagy activation and ultimately ameliorates PTX-induced mitochondrial damage and PIPNP. Furthermore, VASH1 overexpression in DRG neurons reversed the alleviating effects of FGF13 deficiency on PTX-induced mitochondrial damage and PIPNP. In summary, our findings demonstrate that FGF13 deficiency alleviates mitochondrial dysfunction and PIPNP by suppressing VASH1-dependent microtubule detyrosination and subsequently activating Mitophagy. Targeting FGF13 may be a promising therapeutic strategy for PIPNP.