Context dependent roles of FGF13B-NaV1.7 interaction in pain signaling

• Explores FGF13B as a context-dependent regulator of Na V 1.7 channels. • Summarizes conflicting evidence of FGF13B’s effects on Na V 1.7 function. • Proposes FGF13B acts as a regulatory rheostat, not a simple modulator. • Discusses therapeutic potential of targeting the FGF13B/Na V 1.7 interaction. Voltage-gated sodium channels, such as Na V 1.7, serve as pivotal regulators of sensory neuron excitability and nociception. While gain- and loss-of-function mutations in SCN9A cause inherited pain syndromes or congenital insensitivity to pain, the functional regulation of Na V 1.7channels by intracellular protein partners remains incompletely defined. Among these, the fibroblast growth factor 13 isoform B (FGF13B) has emerged as a critical, yet controversial, modulator of Na V 1.7. FGF13B binds the Na V 1.7C-terminal domain, but reported consequences of this interaction appear conflicting, with studies describing both suppression and enhancement of channel function and nociceptor excitability. Here, we review recent genetic, electrophysiological, and pharmacology advances and propose that FGF13B functions as a context-dependent regulatory rheostat of Na V 1.7 rather than as a unidirectional modulator. We highlight how the net functional outcome of this interaction depends on cellular and signaling context and discuss the therapeutic potential of targeting the FGF13B/Na V 1.7complex in pain conditions.