Follistatin (FST) is a multifunctional extracellular regulatory protein that primarily antagonizes members of the transforming growth factor-beta (TGF-β) superfamily, including activin, myostatin, GDF11, and bone morphogenetic proteins 123. Mechanistically, FST binds to these ligands in the extracellular space, blocking their type II receptor-binding sites to inhibit downstream signaling 2. Beyond its classical TGF-β antagonism, FST also functions as an insulin-like growth factor-1 receptor (IGF1R) ligand, where its N-terminal domain directly binds IGF1R to activate extracellular signal-regulated kinase (ERK) and AKT signaling 4. FST plays essential roles in muscle development by suppressing myostatin's repressive effects and promoting neural differentiation through BMP4 antagonism. Additionally, FST acts as a specific inhibitor of follicle-stimulating hormone biosynthesis by sequestering activin A 1. Disease relevance includes neuropathic pain pathogenesis, where FST upregulation in sensory neurons enhances nociceptive neuron hyperexcitability through IGF1R-mediated ERK/AKT activation, with FST inhibition alleviating pain symptoms in mice 4. Clinically, FST's dual signaling capacity through both TGF-β antagonism and IGF1R activation positions it as a potential therapeutic target for pain management and muscle disorders, though its pleiotropic functions necessitate careful consideration of off-target effects.