Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation.

Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells in vitro and in vivo. Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance in vivo. Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.