MBTPS2 is an X-linked zinc metalloprotease that performs intramembrane proteolysis of membrane-bound transcription factors 1. Its primary function involves activating sterol regulatory element-binding proteins (SREBPs) by cleaving them within transmembrane segments, releasing N-terminal fragments that translocate to the nucleus to regulate cholesterol and lipid metabolism 23. MBTPS2 also processes ATF6 and ATF6B during endoplasmic reticulum (ER) stress responses 4, and mediates CREB3L1 activation in response to DNA damage and ER stress, inhibiting cell-cycle progression 5. Beyond cholesterol homeostasis, MBTPS2 functions in bone formation and osteoblast differentiation 6. Mutations in MBTPS2 cause multiple distinct diseases: Ichthyosis Follicularis, Atrichia, and Photophobia syndrome (IFAP) with or without BRESHECK syndrome; Keratosis Follicularis Spinulosa Decalvans; Olmsted syndrome; and Osteogenesis Imperfecta type XIX 1. Different mutations correlate with varying disease severity and phenotypic manifestations 7. Pathogenic variants impair SREBP pathway activation and ER stress responses 8. MBTPS2 dysregulation in prostate cancer promotes lipogenesis and cholesterol synthesis, contributing to metastatic progression 9. The protein also coordinates NF-κB immune signaling with lipogenesis at the Golgi apparatus 10.