SLURP2 is a secreted three-finger protein that functions as a modulator of nicotinic acetylcholine receptor (nAChR) signaling in keratinocytes and other tissues 1. The protein acts through multiple mechanisms: it moderately inhibits acetylcholine-evoked currents in α3β2-containing nAChRs, strongly inhibits α4β2-containing nAChRs, and modulates α7-containing nAChRs via orthosteric interactions, while binding allosterically to muscarinic receptors 2. SLURP2 expression is transcriptionally regulated by IL-22 through STAT3 signaling in keratinocytes, linking it to inflammatory skin responses 3. Loss of SLURP2 causes palmoplantar keratoderma phenotypes including hyperkeratosis, increased keratinocyte proliferation, and lipid accumulation in the stratum corneum 4, similar to SLURP1-deficiency disease manifestations. Functionally, SLURP2 suppresses epithelial cell proliferation through α7-nAChR engagement with nanomolar potency (EC50~0.2 nM) 2. The protein exhibits significant conformational plasticity in its three-finger structural core, enabling optimal interactions with distinct nAChR conformational states 5. Clinically, SLURP2 dysregulation is associated with psoriasis and nasopharyngeal carcinoma prognosis 36, suggesting its importance in epithelial homeostasis and cancer biology.