BRAP maintains SEC24D stability to regulate ER stress and promote cervical adenocarcinoma progression

Cervical adenocarcinoma (ADC) exhibits a poorer prognosis than cervical squamous cell carcinoma and lacks effective targeted therapies. Bombesin receptor- activated protein (BRAP, encoded by C6orf89 ) has been implicated in cell proliferation and stress responses in multiple biological contexts; however, its role in ADC progression and endoplasmic reticulum (ER) homeostasis remains unknown. BRAP expression was evaluated in human cervical adenocarcinoma (ADC) tissues by immunohistochemistry and western blotting, and its clinicopathological significance was analyzed. BRAP function was investigated by siRNA-mediated knockdown in HeLa and SiHa cells using proliferation, apoptosis, migration, invasion, and epithelial–mesenchymal transition (EMT) assays, and further validated in xenograft models. Ultrastructural alterations were examined by transmission electron microscopy. BRAP-interacting proteins were identified by yeast two-hybrid screening and validated by co-immunoprecipitation. ER stress, ER exit site (ERES) homeostasis, and autophagic flux were evaluated, and rescue experiments were performed by re-expression of BRAP or SEC24D. BRAP was markedly upregulated in cervical adenocarcinoma tissues and was associated with poor tumor differentiation. BRAP depletion selectively inhibited proliferation, migration, invasion, and EMT while promoting apoptosis in ADC-derived HeLa cells, but not in squamous cell carcinoma-derived SiHa cells. Mechanistically, BRAP deficiency disrupted ER homeostasis and selectively activated the PERK–ATF4–DDIT3/CHOP branch of the unfolded protein response (UPR), whereas pharmacological inhibition with GSK2606414 largely reversed these phenotypic alterations. We identified the COPII cargo adaptor SEC24D as a novel BRAP-interacting protein. BRAP maintained SEC24D protein stability by preventing excessive autophagy–lysosome-mediated degradation, thereby preserving ERES number and function, as reflected by SEC16A-positive ERES and peripheral LMAN1-positive structures, and maintaining ER–Golgi trafficking homeostasis. Restoration of SEC24D rescued ERES defects, attenuated PERK-dependent UPR activation, and reversed the impaired proliferation, migration, invasion, apoptosis, and EMT induced by BRAP depletion. BRAP promotes cervical adenocarcinoma progression by maintaining SEC24D stability and preserving ERES organization and function, thereby sustaining COPII-dependent ER export and ER homeostasis. Disruption of the BRAP–SEC24D axis impairs ERES integrity, activates PERK-dependent ER stress, and suppresses malignant phenotypes. These findings identify BRAP as a previously unrecognized regulator of ER homeostasis and establish the BRAP–SEC24D signaling axis as a potential therapeutic target for cervical adenocarcinoma.