RNF43 Deficiency Activates YBX1-MYC-Driven Oxidative Phosphorylation in Pancreatic Cancer

RNF43 is frequently inactivated by mutations in pancreatic ductal adenocarcinoma (PDAC), but the molecular mechanisms and therapeutic vulnerabilities associated with RNF43 loss remain poorly defined. Here, we demonstrate that RNF43 functions as an E3 ubiquitin ligase targeting YBX1 for degradation, thereby suppressing mitochondrial oxidative phosphorylation (OXPHOS). In RNF43-deficient PDAC models, stabilized YBX1 activates MYC through dual mechanisms—enhancing MYC mRNA stability via IGF2BP1 and physically interacting with c-Myc protein—leading to transcriptional upregulation of IDH2 and IDH3A and subsequent OXPHOS activation. Importantly, RNF43 loss conferred sensitivity to OXPHOS inhibition both in vitro and in vivo . Treatment with the OXPHOS inhibitor IACS-010759 suppressed the proliferation, migration, invasion, and metastasis of RNF43-mutant tumors. Our findings identify a RNF43–YBX1–MYC signaling axis associated with metabolic reprogramming in pancreatic cancer and suggest that OXPHOS inhibition may represent a potential therapeutic vulnerability in tumors with RNF43-inactivating mutations. • RNF43 directly ubiquitinates and degrades YBX1 to suppress PDAC progression. • The RNF43-YBX1 axis regulates MYC-mediated oxidative phosphorylation. • RNF43 inactivation renders pancreatic cancer sensitive to OXPHOS inhibitors. • Targeting mitochondrial respiration is effective in RNF43-mutant PDAC models.