Open Access
ARTICLE
Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer
Jinhui Che1,2, Zhiyuan Chen1, Feng Zhang3,4, Shuo Zhu2, Shengya Cao5, Ou Li1, Rong Li4,*, Jun Zheng3,4,*, Yubin Liu1,*
1 Department of Hepatobiliary Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
2 Department of Hepatobiliary Surgery, Xuzhou Cancer Hospital, Xuzhou, China
3 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
4 Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
5 Department of Clinical Laboratory, Xuzhou Cancer Hospital, Xuzhou, China
* Corresponding Author: Rong Li. Email: 
; Jun Zheng. Email: 
; Yubin Liu. Email: 
(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)
Oncology Research https://doi.org/10.32604/or.2026.067443
Received 03 May 2025; Accepted 14 April 2026; Published online 05 May 2026
Abstract
Objective: Advanced liver cancer, a highly lethal and increasingly prevalent malignancy, frequently develops sorafenib resistance, with aberrant mitochondrial dynamics and metabolism implicated in its pathogenesis. This study aimed to investigate their interplay and assess combination therapies against sorafenib-resistant liver cancer. Methods: Mitochondrial morphology was assessed using immunofluorescent staining. Besides, the mitochondrial metabolic profile was evaluated by measuring the oxygen consumption rate, glucose uptake, and lactate production. Dynamin-related protein 1 (Drp1) expression was determined through immunohistochemical staining, western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting, colony formation, and cell cycle assays were conducted to evaluate in vitro cell growth. Furthermore, time-lapse cell motility and Transwell assays were employed to assess cell migration and invasion capacities, respectively. Orthotopic xenograft models were utilized to demonstrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 and the Drp1 inhibitor mdivi-1. Result: Importantly, our findings revealed that Drp1-mediated mitochondrial fission and the metabolic switch from OXPHOS to aerobic glycolysis were dominant in sorafenib-resistant liver cancer cells and strongly correlated with tumor prognosis (hazard ratio = 3.899, 95% confidence interval: 1.167–13.022, p = 0.027). Drp1 knockdown or inhibition impaired the invasive and metastatic capabilities of these cancer cells but promoted cell cycle progression and cellular growth, attributed to a metabolic shift from aerobic glycolysis to OXPHOS. Notably, the combined administration of the OXPHOS inhibitor IACS-010759 with mdivi-1 significantly attenuated tumor progression in sorafenib-resistant liver cancer, affecting both proliferation and metastasis. Conclusion: The results of this study collectively indicate that mitochondrial dynamics regulate metabolism in sorafenib-resistant liver cancer, which displays an aggressive hybrid metabolic phenotype. Accordingly, the combined targeting of mitochondrial dynamics and metabolism may represent an effective strategy to overcome sorafenib resistance in liver cancer.
Keywords
Sorafenib-resistant hepatocellular carcinoma; mitochondrial dynamics; glucose metabolism; mdivi-1; IACS-010759
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