NCSTN (nicastrin) is an essential subunit of the gamma-secretase complex, a transmembrane protease that catalyzes intramembrane cleavage of key signaling proteins including Notch receptors and amyloid-beta precursor protein (APP). This activity regulates Notch and Wnt/β-catenin signaling pathways, which control epidermal keratinization and other developmental processes. NCSTN mutations are associated with monogenic hidradenitis suppurativa (HS), a chr1 inflammatory skin disease. In a Maltese cohort, the NCSTN:c.671_682del variant was identified in 12.4% of HS patients, conferring earlier disease onset and atypical phenotype affecting the scalp, neck, torso, and antecubital fossae 1. Carriers of this deletion show elevated serum immunoglobulin G levels, suggesting altered humoral immunity as a mechanistic link 2. A genome-wide association meta-analysis of 4814 HS cases identified NCSTN among candidate causal genes disrupting epidermal keratinization pathways 3. In mouse models, NCSTN mutations disrupt hair follicle structure and downregulate hair cortex proteins, recapitulating HS-like lesions 4. In hepatocellular carcinoma, elevated NCSTN expression correlates with worse prognosis and promotes tumor growth and metastasis via Notch1/AKT-dependent β-catenin activation 5. Gamma-secretase inhibitors including semagacestat, nirogacestat, and avagacestat have been evaluated as therapeutic approaches targeting this pathway in disease contexts.