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RNF43 deficiency activates YBX1-MYC-driven oxidative phosphorylation in pancreatic cancer
Gengdu Qin1, Penglin Pan1, Yang Qin2
1Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cancer Letters
|May 7, 2026
Summary
Loss of RNF43 in pancreatic cancer stabilizes YBX1, activating MYC and boosting oxidative phosphorylation (OXPHOS). This metabolic shift makes RNF43-mutant tumors vulnerable to OXPHOS inhibitors for potential therapy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- RNF43 mutations are common in pancreatic ductal adenocarcinoma (PDAC).
- The precise molecular functions and therapeutic implications of RNF43 loss in PDAC are not fully understood.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms by which RNF43 inactivation impacts PDAC.
- To identify potential therapeutic vulnerabilities associated with RNF43 loss.
- To investigate the role of the RNF43-YBX1-MYC axis in pancreatic cancer metabolism.
Main Methods:
- Utilized RNF43-deficient PDAC models.
- Investigated the interaction between RNF43, YBX1, and MYC.
- Assessed the impact of RNF43 loss on mitochondrial oxidative phosphorylation (OXPHOS).
- Evaluated the efficacy of the OXPHOS inhibitor IACS-010759 in vitro and in vivo.
Main Results:
- RNF43 acts as an E3 ubiquitin ligase that targets YBX1 for degradation, suppressing OXPHOS.
- RNF43 deficiency leads to YBX1 stabilization, which activates MYC via enhanced mRNA stability and direct protein interaction.
- MYC upregulation results in increased expression of IDH2 and IDH3A, promoting OXPHOS.
- RNF43-mutant PDAC models showed increased sensitivity to OXPHOS inhibition.
- IACS-010759 treatment reduced proliferation, migration, invasion, and metastasis in RNF43-mutant tumors.
Conclusions:
- A novel RNF43-YBX1-MYC signaling axis drives metabolic reprogramming in pancreatic cancer.
- RNF43 inactivation promotes OXPHOS through YBX1 stabilization and MYC activation.
- Inhibition of OXPHOS presents a promising therapeutic strategy for pancreatic tumors with RNF43-inactivating mutations.
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