{"doi":"10.1172/jci183749","title":"Sensory neuron–expressed FGF13 controls nociceptive signaling in diabetic neuropathy models","abstract":"Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 ligand that stabilizes FGF13/Nav1.7 CTD assembly, sensitized Na+ currents in hIPSC-derived sensory neurons and exerted pronociceptive behavioral responses in mice. ZL192's effects were abrogated by FGF13 silencing in culture and in vivo and recapitulated by FGF13 overexpression. In a model of T2DN, PW164 injection reduced mechanical hyperalgesia locally and contralaterally without systemic side effects. In donor-derived dorsal root ganglia neurons, FGF13 and Nav1.7 proteins colocalized, and the FGF13/Nav1.7 protein ratio was upregulated in patients with T2DN. Lastly, we found that SCN9A variant V1831F, associated with painless diabetic neuropathy, abolished PW164-directed modulation of the FGF13/Nav1.7 PPI interface. Thus, FGF13 is a rheostat of nociception and promising therapeutic target for diabetic neuropathy pain.","journal":"Journal of Clinical Investigation","year":2025,"id":514383,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":59053,"name":"Matteo Bernabucci","orcid":"0000-0003-4458-117X","position":1,"is_corresponding":false},{"id":383915,"name":"Nolan M. 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