PSENEN encodes the smallest essential subunit of the γ-secretase complex, an intramembrane protease that cleaves integral membrane proteins including APP and Notch receptors 1. PSENEN is indispensable for γ-secretase complex formation and enzymatic activity, with glycine 22 and proline 27 being critical for complex stabilization 1. The protein contains hairpin-structured hydrophobic membrane domains exposed to a water-containing cavity within the complex, contributing to the catalytic mechanism 1. Beyond its proteolytic role, PSENEN functions in the autophagy-lysosome system independently of γ-secretase activity, affecting lysosomal enzyme activity and autophagosome-lysosome fusion 2. PSENEN also serves as a binding partner for metformin, forming complexes with ATP6AP1 that lead to v-ATPase inhibition and AMPK activation 3. Loss-of-function mutations in PSENEN cause familial acne inversa (hidradenitis suppurativa) and Dowling-Degos disease, conditions characterized by inflammatory skin lesions and reticulate hyperpigmentation 456. Genome-wide association studies have identified PSENEN variants as risk factors for hidradenitis suppurativa, highlighting its role in epidermal keratinization through Notch and Wnt/β-catenin signaling pathways 7. The gene is co-regulated with U2AF1L4 by a bidirectional promoter, potentially important for T-cell activity regulation 8.