8‐Oxoguanine Modified CircMTUS1 Drives PABPC1 Phase Separation to Promote Gastric Cancer Progression and Cisplatin Resistance via Autophagy

ABSTRACT Gastric cancer (GC) is a major global health concern, as its prevention and treatment remain significant challenges. The 8‐oxoguanine (o8G) modification of circRNAs, alongside their capacity to orchestrate liquid‐liquid phase separation (LLPS) and autophagy, plays a pivotal role in driving tumor progression and determining therapeutic outcomes. Here, we identified the downregulation of circMTUS1 in GC and elucidated the upstream and downstream mechanisms governing its role in tumor progression and chemoresistance. We demonstrated that YBX1 induces o8G modification, which reduces circMTUS1 stability. Notably, circMTUS1 restoration markedly inhibits tumor growth both in vitro and in vivo. Mechanistically, circMTUS1 targeted PABPC1 through the LLPS to regulate stress granules (SG) formation and autophagy to inhibit GC progression and to affect the sensitivity to chemotherapy. Furthermore, the small‐molecule SG inhibitor ISRIB acts synergistically with circMTUS1 to significantly sensitize GC cells to cisplatin. Collectively, our data demonstrate that circMTUS1 suppresses GC progression through a pathway involving YBX1‐dependent o8G modification and PABPC1‐mediated regulation of SG and autophagy. Consequently, targeting circMTUS1 or its downstream SG may offer an effective strategy to enhance the chemosensitivity of gastric cancer.