RHBDD2 (rhomboid domain containing 2) is a catalytically inactive rhomboid pseudoprotease localized to the Golgi apparatus and endoplasmic reticulum 1. Primary function: RHBDD2 modulates protein trafficking and cell signaling through protein-protein interactions, including binding to WWOX (via its conserved C-terminal LPPY motif) and the UPR master regulator BiP 23. Mechanism: RHBDD2 regulates the unfolded protein response (UPR) pathway and modulates cell proliferation through interaction with signaling proteins. It suppresses expression of UPR genes (ATF6, IRE1, PERK, CHOP, BiP) and inhibits TGFβ/SMAD3 signaling, thereby promoting cell proliferation and migration 42. Disease Relevance: RHBDD2 is markedly overexpressed in advanced-stage breast cancer, colorectal cancer, and cervical cancer, with gene amplification detected in 21% of invasive breast carcinomas 56. High RHBDD2 expression correlates with poor prognosis, decreased survival, and metastasis 5. A homozygous R85H mutation associates with autosomal recessive retinitis pigmentosa 1. Clinical Significance: RHBDD2 overexpression confers chemoresistance to 5-fluorouracil and cisplatin through UPR modulation and elevated drug transporter expression, positioning RHBDD2 as a prognostic biomarker for treatment response prediction 37. MicroRNA-4739 suppression of RHBDD2 restores chemosensitivity, suggesting therapeutic potential 7.