Sorafenib Restores Pentose Phosphate Pathway-Related Redox Homeostasis via the c-Raf/HSP90/G6PD Axis in Hepatic Ischemia-Reperfusion Injury

Abstract

Hepatic ischemia reperfusion injury (IRI) is a frequent complication of liver surgery and is strongly associated with poorer recipient survival. Sorafenib, a multi-kinase inhibitor, has been implicated in hepatic metabolic and redox regulation, yet its role in hepatic IRI remains unclear. Our study finds that middle-dose sorafenib protects the liver from IRI by reducing hepatic necrosis, inflammation, and apoptosis. Mechanistically, transcriptomic and metabolomics analyses confirm that middle-dose sorafenib enhances pentose phosphate pathway-mediated antioxidant activity through the c-rapidly accelerated fibrosarcoma (c-Raf)/heat shock protein 90 (HSP90)/glucose-6-phosphate dehydrogenase (G6PD) axis. Co-immunoprecipitation, Western blot, and confocal immunofluorescence analyses demonstrate the direct binding interaction between HA-c-Raf and Myc-HSP90, as well as between Flag-G6PD and Myc-HSP90. Meanwhile, the overexpression of HSP90 disrupts the benefits of sorafenib on hepatic IRI, and inhibition of G6PD also rescues its protective effect. Notably, in human liver transplant recipients, elevated HSP90 levels correlated with poor graft function and survival, supporting its clinical relevance. Furthermore, a novel oral nanoparticle delivery system, targeting the liver tissue, enhances the therapeutic efficacy of sorafenib, restoring liver enzyme levels by up to 76%. Collectively, these findings identify middle-dose sorafenib, particularly when delivered via the novel oral nanoplatform, as an effective strategy to mitigate hepatic IRI.

Keywords

liver ischemia-reperfusion injury / pentose phosphate pathway / redox homeostasis / sorafenib

References

[1] A. D. Bostom, R. S. Brown Jr, B. M. Chavers, et al., “Prevention of Post-Transplant Cardiovascular Disease–Report and Recommendations of an Ad Hoc Group,” American Journal of Transplantation 2, no. 6 (2002): 491–500.

[2] C. X. Zhu, L. Yang, H. Zhao, et al., “Impact of Cirrhosis-Related Complications on Posttransplant Survival in Patients With Acute-On-Chronic Liver Failure,” Hepatobiliary & Pancreatic Diseases International 22, no. 1 (2023): 64–71.

[3] H. Liu and K. Man, “New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation,” International Journal of Molecular Sciences 22, no. 15 (2021): 8210.

[4] S. Yu, K. Wang, Q. Li, et al., “Nonalcoholic Steatohepatitis Critically Rewires the Ischemia/Reperfusion-Induced Dysregulation of Cardiolipins and Sphingolipids in Mice,” HepatoBiliary Surgery and Nutrition 12, no. 1 (2023): 3–19.

[5] M. Y. Wu, G. T. Yiang, W. T. Liao, et al., “Current Mechanistic Concepts in Ischemia and Reperfusion Injury,” Cellular Physiology and Biochemistry 46, no. 4 (2018): 1650–1667.

[6] K. J. Dery, H. Kojima, S. Kageyama, et al., “Alternative Splicing of CEACAM1 by Hypoxia-Inducible Factor-1alpha Enhances Tolerance to Hepatic Ischemia in Mice and Humans,” Science Translational Medicine 15, no. 707 (2023): eadf2059.

[7] H. Y. Zhou, T. Li, and Y. Q. Lu, “Baicalin and Its Nanoliposome Ameliorate Diquat-Induced Liver Injury by Promoting PINK1/Parkin-Dependent Mitophagy,” Hepatobiliary & Pancreatic Diseases International 24, no. 5 (2025): 527–534.

[8] F. Gao, X. Qiu, K. Wang, et al., “Targeting the Hepatic Microenvironment to Improve Ischemia/Reperfusion Injury: New Insights Into the Immune and Metabolic Compartments,” Aging and Disease 13, no. 4 (2022): 1196–1214.

[9] Y. Wu, C. Li, A. A. Khan, et al., “Insulin-Induced Gene 2 Protects Against Hepatic Ischemia-Reperfusion Injury via Metabolic Remodeling,” Journal of Translational Medicine 21, no. 1 (2023): 739.

[10] Y. Zhai, R. W. Busuttil, and J. W. Kupiec-Weglinski, “Liver Ischemia and Reperfusion Injury: New Insights Into Mechanisms of Innate-Adaptive Immune-Mediated Tissue Inflammation,” American Journal of Transplantation 11, no. 8 (2011): 1563–1569.

[11] D. J. Hausenloy and D. M. Yellon, “Ischaemic Conditioning and Reperfusion Injury,” Nature Reviews Cardiology 13, no. 4 (2016): 193–209.

[12] R. A. Elrashidy, E. M. Zakaria, R. A. Hasan, et al., “Implication of Endoplasmic Reticulum Stress and Mitochondrial Perturbations in Remote Liver Injury After Renal Ischemia/Reperfusion in Rats: Potential Protective Role of Azilsartan,” Redox Report: Communications in Free Radical Research 29, no. 1 (2024): 2319963.

[13] D. E. Elsayed Abouzed, H. A. A. Ezelarab, H. Selim, M. M. A. Elsayed, M. A. El Hamd, and M. O. Aboelez, “Multimodal Modulation of Hepatic Ischemia/Reperfusion-Induced Injury by Phytochemical Agents: A Mechanistic Evaluation of Hepatoprotective Potential and Safety Profiles,” International Immunopharmacology 138 (2024): 112445.

[14] Y. Chen, H. Li, P. Wen, et al., “Pharmacological Inhibition of ENaC or NCX Can Attenuate Hepatic Ischemia-Reperfusion Injury Exacerbated by Hypernatremia,” Journal of Zhejiang University Science B 26, no. 5 (2025): 461–476.

[15] M. O. Aboelez, H. A. A. Ezelarab, G. Alotaibi, and D. E. E. Abouzed, “Inflammatory Setting, Therapeutic Strategies Targeting Some Pro-Inflammatory Cytokines and Pathways in Mitigating Ischemia/Reperfusion-Induced Hepatic Injury: A Comprehensive Review,” Naunyn-Schmiedebergs Archives of Pharmacology 397, no. 9 (2024): 6299–6315.

[16] Q. Li, X. Qin, L. Wang, et al., “Multi-Time Point Transcriptomics and Metabolomics Reveal Key Transcription and Metabolic Features of Hepatic Ischemia-Reperfusion Injury in Mice,” Genes & Diseases 12, no. 2 (2025): 101465.

[17] T. TeSlaa, M. Ralser, J. Fan, and J. D. Rabinowitz, “The Pentose Phosphate Pathway in Health and Disease,” Nature Metabolism 5, no. 8 (2023): 1275–1289.

[18] A. M. Scantlebery, A. Tammaro, J. D. Mills, et al., “The Dysregulation of Metabolic Pathways and Induction of the Pentose Phosphate Pathway in Renal Ischaemia-Reperfusion Injury,” Journal of Pathology 253, no. 4 (2021): 404–414.

[19] J. Chen, R. Jin, J. Zhao, et al., “Potential Molecular, Cellular and Microenvironmental Mechanism of Sorafenib Resistance in Hepatocellular Carcinoma,” Cancer Letters 367, no. 1 (2015): 1–11.

[20] W. Tang, Z. Chen, W. Zhang, et al., “The Mechanisms of Sorafenib Resistance in Hepatocellular Carcinoma: Theoretical Basis and Therapeutic Aspects,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 87.

[21] J. M. Llovet, S. Ricci, V. Mazzaferro, et al., “Sorafenib in Advanced Hepatocellular Carcinoma,” New England Journal of Medicine 359, no. 4 (2008): 378–390.

[22] A. L. Cheng, Y. K. Kang, Z. Chen, et al., “Efficacy and Safety of Sorafenib in Patients in the Asia-Pacific Region With Advanced Hepatocellular Carcinoma: A Phase III Randomised, Double-Blind, Placebo-Controlled Trial,” The Lancet Oncology 10, no. 1 (2009): 25–34.

[23] A. B. El-Khoueiry, J. Trojan, T. Meyer, et al., “Nivolumab in Sorafenib-Naive and Sorafenib-Experienced Patients With Advanced Hepatocellular Carcinoma: 5-Year Follow-Up From CheckMate 040,” Annals of Oncology 35, no. 4 (2024): 381–391.

[24] S. Martens, M. Jeong, W. Tonnus, et al., “Sorafenib Tosylate Inhibits Directly Necrosome Complex Formation and Protects in Mouse Models of Inflammation and Tissue Injury,” Cell Death & Disease 8, no. 6 (2017): e2904.

[25] P. S. Welz, A. Wullaert, K. Vlantis, et al., “FADD Prevents RIP3-Mediated Epithelial Cell Necrosis and Chronic Intestinal Inflammation,” Nature 477, no. 7364 (2011): 330–334.

[26] C. Jian, J. Fu, X. Cheng, et al., “Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis,” Cell Metabolism 31, no. 6 (2020): 1206.

[27] S. Yuan, C. Wei, G. Liu, et al., “Sorafenib Attenuates Liver Fibrosis by Triggering Hepatic Stellate Cell Ferroptosis via HIF-1alpha/SLC7A11 Pathway,” Cell Proliferation 55, no. 1 (2022): e13158.

[28] L. Li, L. Wang, Q. D. You, and X. L. Xu, “Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions,” Journal of Medicinal Chemistry 63, no. 5 (2020): 1798–1822.

[29] S. Garcia-Alonso, P. Mesa, L. P. Ovejero, et al., “Structure of the RAF1-HSP90-CDC37 Complex Reveals the Basis of RAF1 Regulation,” Molecular Cell 82, no. 18 (2022): 3438–3452.e8.

[30] C. Jian, J. Fu, X. Cheng, et al., “Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis,” Cell Metabolism 31, no. 5 (2020): 892–908.e11.

[31] R. Ma, J. Chen, Y. Liang, et al., “Sorafenib: A Potential Therapeutic Drug for Hepatic Fibrosis and Its Outcomes,” Biomedicine & Pharmacotherapy 88 (2017): 459–468.

[32] R. Li, J. Zhang, Q. Liu, et al., “CREKA-Modified Liposomes Target Activated Hepatic Stellate Cells to Alleviate Liver Fibrosis by Inhibiting Collagen Synthesis and Angiogenesis,” Acta Biomaterialia 168 (2023): 484–496.

[33] C. Li, Y. Wu, K. Chen, et al., “Gp78 Deficiency in Hepatocytes Alleviates Hepatic Ischemia-Reperfusion Injury via Suppressing ACSL4-Mediated Ferroptosis,” Cell Death & Disease 14, no. 12 (2023): 810.

[34] X. J. Zhang, X. Cheng, Z. Z. Yan, et al., “An ALOX12-12-HETE-GPR31 Signaling Axis Is a Key Mediator of Hepatic Ischemia-Reperfusion Injury,” Nature Medicine 24, no. 1 (2018): 73–83.

[35] R. Ding, W. Wu, Z. Sun, and Z. Li, “AMP-Activated Protein Kinase: An Attractive Therapeutic Target for Ischemia-Reperfusion Injury,” European Journal of Pharmacology 888 (2020): 173484.

[36] G. Tong, Y. Chen, X. Chen, et al., “FGF18 Alleviates Hepatic Ischemia-Reperfusion Injury via the USP16-Mediated KEAP1/Nrf2 Signaling Pathway in Male Mice,” Nature Communications 14, no. 1 (2023): 6107.

[37] R. G. Bardallo, A. Panisello-Rosello, S. Sanchez-Nuno, N. Alva, J. Rosello-Catafau, and T. Carbonell, “Nrf2 and Oxidative Stress in Liver Ischemia/Reperfusion Injury,” Febs Journal 289, no. 18 (2022): 5463–5479.

[38] B. Chen, W. H. Piel, L. Gui, E. Bruford, and A. Monteiro, “The HSP90 Family of Genes in the Human Genome: Insights Into Their Divergence and Evolution,” Genomics 86, no. 6 (2005): 627–637.

[39] Y. Liu, L. Zhou, Y. Xu, et al., “Heat Shock Proteins and Ferroptosis,” Frontiers in Cell and Developmental Biology 10 (2022): 864635.

[40] S. O'Neill, J. A. Ross, S. J. Wigmore, and E. M. Harrison, “The Role of Heat Shock Protein 90 in Modulating Ischemia-Reperfusion Injury in the Kidney,” Expert Opinion on Investigational Drugs 21, no. 10 (2012): 1535–1548.

[41] C. Prodromou and L. H. Pearl, “Structure and Functional Relationships of Hsp90,” Current Cancer Drug Targets 3, no. 5 (2003): 301–323.

[42] G. Watanabe, K. E. Behrns, J. S. Kim, and R. D. Kim, “Heat Shock Protein 90 Inhibition Abrogates Hepatocellular Cancer Growth Through cdc2-Mediated G2/M Cell Cycle Arrest and Apoptosis,” Cancer Chemotherapy and Pharmacology 64, no. 3 (2009): 433–443.

[43] H. Tian, X. Zhao, Y. Zhang, and Z. Xia, “Abnormalities of Glucose and Lipid Metabolism in Myocardial Ischemia-Reperfusion Injury,” Biomedicine & Pharmacotherapy 163 (2023): 114827.

[44] P. Wang, Y. Cui, Y. Liu, et al., “Mitochondrial Ferritin Alleviates Apoptosis by Enhancing Mitochondrial Bioenergetics and Stimulating Glucose Metabolism in Cerebral Ischemia Reperfusion,” Redox Biology 57 (2022): 102475.

[45] Z. Guo, J. Xu, S. Huang, et al., “Abrogation of Graft Ischemia-Reperfusion Injury in Ischemia-Free Liver Transplantation,” Clinical and Translational Medicine 12, no. 4 (2022): e546.

[46] Q. Meng, Y. Zhang, S. Hao, et al., “Recent Findings in the Regulation of G6PD and Its Role in Diseases,” Frontiers in Pharmacology 13 (2022): 932154.

[47] J. Liu and K. Man, “Mechanistic Insight and Clinical Implications of Ischemia/Reperfusion Injury Post Liver Transplantation,” Cellular and Molecular Gastroenterology & Hepatology 15, no. 6 (2023): 1463–1474.

[48] H. Hirao, K. Nakamura, and J. W. Kupiec-Weglinski, “Liver Ischaemia-Reperfusion Injury: A New Understanding of the Role of Innate Immunity,” Nature Reviews Gastroenterology & Hepatology 19, no. 4 (2022): 239–256.

[49] A. Parente, F. Tirotta, A. Pini, et al., “Machine Perfusion Techniques for Liver Transplantation—A Meta-Analysis of the First Seven Randomized-Controlled Trials,” Journal of Hepatology 79, no. 5 (2023): 1201–1213.

[50] S. J. Tingle, J. J. Dobbins, E. R. Thompson, et al., “Machine Perfusion in Liver Transplantation,” Cochrane Database of Systematic Reviews 9, no. 9 (2023): CD014685.

[51] G. G. Panayotova, K. E. Lunsford, R. C. Quillin 3rd, et al., “Portable Hypothermic Oxygenated Machine Perfusion for Organ Preservation in Liver Transplantation: A Randomized, Open-Label, Clinical Trial,” Hepatology 79, no. 5 (2024): 1033–1047.

[52] W. Fan, Q. Wei, J. Xiang, et al., “Mucus Penetrating and Cell-Binding Polyzwitterionic Micelles as Potent Oral Nanomedicine for Cancer Drug Delivery,” Advanced Materials 34, no. 16 (2022): e2109189.

Rights & permissions

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.