MBTPS1 (membrane-bound transcription factor peptidase, site 1) is a serine protease located on chromosome 16 that catalyzes regulated intramembrane proteolysis of multiple substrates. Its primary function involves cleaving membrane-bound transcription factors after specific hydrophobic residue motifs 1. MBTPS1 catalyzes the initial proteolytic activation of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2, which regulate cholesterol and lipid homeostasis 23. Additional substrates include activating transcription factor 6 (ATF6), CREB3L1, BDNF, and FAM20C, implicating MBTPS1 in ER stress response, bone mineralization, and lysosomal biogenesis 45. Mechanistically, MBTPS1 operates sequentially with site-2 protease (MBTPS2) to regulate cholesterol metabolism and endoplasmic reticulum stress responses 6. Notably, MBTPS1 also regulates antitumor immunity independently of its classical transcription factor cleavage function, competing with USP13 for STAT1 binding to modulate chemokine expression and CD8+ T cell infiltration 7. Pathogenic MBTPS1 variants cause multiple clinically distinct disorders including spondyloepiphyseal dysplasia (Kondo-Fu type), cataract-alopecia-oral mucosal disorder-psoriasis syndrome (CAOP), and Silver-Russell-like syndrome, with emerging phenotypes including white matter abnormalities and ectodermal dysplasia 16. MBTPS1 dysfunction disrupts lipid metabolism pathways critical for cancer cell proliferation, suggesting therapeutic potential for colorectal cancer 37.