RHBDD2 is a catalytically inactive rhomboid pseudoprotease that localizes to the Golgi apparatus and endoplasmic reticulum membranes, where it modulates protein trafficking and stress responses. The protein interacts with WWOX to regulate TGFβ/SMAD3 signaling and epithelial cell proliferation 1. RHBDD2 is prominently involved in cancer biology: it is consistently overexpressed in advanced stages of breast cancer, colorectal cancer, and rectal cancer, with gene amplification detected in 21% of invasive breast carcinomas but absent in normal tissue 2. In rectal cancer, RHBDD2 overexpression confers chemoresistance to 5-fluorouracil and promotes an invasive phenotype by binding to the unfolded protein response (UPR) regulator BiP and modulating expression of UPR genes (BiP, PERK, CHOP) and focal adhesion molecules (FAK, PXN) 3. In cervical cancer, cisplatin resistance is mediated by elevated RHBDD2, which is negatively regulated by microRNA-4739 4. High RHBDD2 expression associates with poor prognosis in ER-negative breast cancer, including decreased overall survival and metastasis-free interval 2. RHBDD2 is also identified as a component of lung adenocarcinoma prognostic models based on ER stress-related gene signatures 5. A homozygous R85H mutation in RHBDD2 co-segregates with autosomal recessive retinitis pigmentosa, suggesting roles in photoreceptor development and function 6.