RHBDL2 is an intramembrane serine protease that regulates cellular signaling through proteolytic cleavage of transmembrane substrates. The enzyme functions as a proenzyme requiring processing for activation, with a conserved arginine residue in loop 1 being critical for this activation process 1. RHBDL2 cleaves diverse substrates including Notch1, Orai1 calcium channels, thrombomodulin, IL-6 receptor, and various cell adhesion molecules 2345. The protease performs conformational surveillance of Orai1 calcium channels, preventing inappropriate activation and maintaining proper calcium signaling in unstimulated cells 3. In wound healing, RHBDL2 cleaves thrombomodulin to release soluble forms that promote keratinocyte migration and tissue repair 4. Clinically, RHBDL2 is overexpressed in multiple cancers including pancreatic cancer and clear cell renal cell carcinoma, where it promotes proliferation, metastasis, and poor patient outcomes through activation of Notch and Wnt/β-catenin pathways 26. The protease also inhibits cuproptosis-related genes and affects tumor immune microenvironment infiltration 6. These findings establish RHBDL2 as a critical regulator of epithelial homeostasis with significant therapeutic potential in cancer treatment.