A new layer of pain regulation: FGF13 control of Nav1.7 in sensory neurons
Aims: In this study, Singh et al. investigated the role of fibroblast growth factor 13 (FGF13) in regulating nociceptive signaling in sensory neurons. Specifically, they aimed to determine how the interaction between FGF13 and the voltage-gated sodium channel Nav1.7 contributes to pain modulation, and whether this pathway is altered in diabetic neuropathy.
Methods: The authors combined structure-guided drug design, electrophysiology, and in vivo behavioral approaches. They identified small molecules that either disrupt (PW164) or stabilize (ZL192) the FGF13/Nav1.7 protein–protein interaction. Human iPSC-derived sensory neurons and HEK293 cells expressing Nav1.7 were used for patch-clamp recordings. In vivo validation was performed in mice using capsaicin-induced pain and high-fat diet–induced type 2 diabetic neuropathy models. Additionally, human dorsal root ganglia (DRG) samples and transcriptomic datasets were analyzed to confirm translational relevance.
Results: The study demonstrates that FGF13 acts as a bidirectional regulator of nociception through its interaction with Nav1.7. Disruption of this complex with PW164 reduced sodium currents and selectively suppressed capsaicin-induced hyperexcitability in sensory neurons, without affecting baseline sensory function. In vivo, PW164 reduced mechanical and thermal hyperalgesia, including in diabetic neuropathy models, and showed no major systemic side effects.
Conversely, stabilization of the FGF13/Nav1.7 complex with ZL192 enhanced sodium currents and induced pronociceptive responses in vitro and in vivo. Genetic silencing of FGF13 mimicked the analgesic effects of PW164, while FGF13 overexpression reproduced hypersensitivity phenotypes. Importantly, human DRG neurons showed co-expression of FGF13 and Nav1.7, and an increased FGF13/Nav1.7 ratio was observed in patients with diabetic neuropathy, suggesting enhanced complex formation in disease.
Conclusions: Together, these findings identify FGF13 as a key “rheostat” of nociception that bidirectionally regulates Nav1.7 activity. Targeting the FGF13/Nav1.7 interaction represents a promising therapeutic strategy for treating diabetic neuropathic pain while preserving normal sensory function.
Comments: This study presents a well-supported mechanism positioning FGF13 as a regulator of nociceptive signaling through its interaction with Nav1.7. The integration of pharmacological, genetic, and human data strengthens the overall conclusions and highlights the translational relevance of the findings. While further work will be needed to explore long-term effects and therapeutic feasibility, the approach offers an interesting alternative to direct sodium channel blockade. Overall, this work provides a thoughtful and promising contribution to the field of pain research, particularly in the context of diabetic neuropathy.
Stéphanie Eid
Reference. Singh AK, Bernabucci M, Dvorak NM, Haghighijoo Z, Di Re J, Goode NA, Kadakia FK, Maile LA, Folorunso OO, Wadsworth PA, Tapia CM, Wang P, Wang J, Chen H, Xue Y, Singh J, Hankerd K, Gamez IJ, Kager M, Truong V, Walsh P, Shiers SI, Kuttanna N, Liao H, Marchi M, Salvi E, D'Amato I, D'Amico D, Arman P, Faber CG, Malik RA, de Tommaso M, Ziegler D, Rajarathnam K, Green TA, Grace PM, Sapio MR, Iadarola MJ, Cuny GD, Chow DS, Lauria Pinter G, Davidson S, Green DP, La JH, Chung JM, Zhou J, Price TJ, Salisbury E, Yuan S, Laezza F. Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models. J Clin Invest. 2025 Jul 15;135(14):e183749. doi: 10.1172/JCI183749. PMID: 40662354; PMCID: PMC12259270.
