IGFBPL1 in DRG nociceptors drives neuropathic pain and neuroimmune crosstalk via IGF1R–ERK signaling

Neuronal hyperexcitability and neuroimmune dysregulation are central hallmarks of neuropathic pain. Insulin-like growth factor binding protein-like 1 (IGFBPL1), a secreted glycoprotein and classical member of the insulin-like growth factor binding protein (IGFBP) family, has been implicated in γ-aminobutyric acid (GABA)-ergic circuits, neurite outgrowth, and immune modulation in the central nervous system (CNS); however, its functional role in the peripheral nervous system (PNS), particularly in the somatosensory system, remains unexplored. Here, we report that IGFBPL1 is increased in the dorsal root ganglion (DRG) following peripheral nerve injury, and that this increase contributes to the development and maintenance of neuropathic pain. We show that IGFBPL1 upregulation in DRG sensory neurons induces pain behaviors and neuronal hyperexcitability through insulin-like growth factor 1 receptor (IGF1R)–extracellular signal-regulated kinase (ERK) signaling and drives macrophage recruitment. Conversely, Igfbpl1 -specific knockdown or pharmacological inhibition alleviates pain hypersensitivity, normalizes neuronal hyperexcitability, and reduces macrophage infiltration and neuroimmune crosstalk. Notably, Igfbpl1 -specific knockdown also improved gait performance in chronic constriction injury (CCI) mice. Our findings identify IGFBPL1 as a critical regulator of DRG pathophysiology, linking growth factor signaling, sensory neuron plasticity, and neuroimmune interactions in neuropathic pain.