Mechanistic Insights into the Diabetes–Cirrhosis–Hepatocellular Carcinoma Axis: Molecular Mechanisms and Therapeutic Perspectives
DOI:
https://doi.org/10.62382/jcbt.v3i2.117Keywords:
Hepatocellular carcinoma, Glucose metabolism, Oxidative stress, Liver cancerAbstract
Hepatocellular carcinoma (HCC) cellular metabolism is also directed toward glycolysis in order to improve the synthesis of metabolic chemicals utilized by cancer cells to produce proteins, lipids, and nucleotides and maintain a high rate of cell proliferation. Several hepatic conditions are strongly associated with diabetes mellitus (DM), including non-alcoholic fatty liver disease (NAFLD), steatohepatitis, and liver cirrhosis. Recent findings also support that DM can predispose individuals to various forms of malignant neoplasm including renal, endometrial, breast, gallbladder, colorectal, pancreatic, and liver cancer likewise the HCC. This process promotes uncontrolled cellular proliferation and increases reactive oxygen species (ROS) production, contributing to cellular damage, which may cause cell death. Numerous risk factors of both DM and cancer share so much, yet the relationship between the two is imprecisely stated. Some epidemiologic studies have established a correlation between pathogenic and prognostic attributes of DM and increased incidence of HCC and, therefore, depict DM as a single risk factor in the development of HCC. The etiological and pathophysiological relationship between DM and HCC has been given in this review, which links hyperglycemia, hyperinsulinemia, insulin resistance, and the activation of insulin-like growth factor (IGF) signaling pathway and pharmacological treatment of the HCC in DM. The HCC treatment targets in these pathways, hyperinsulinemia, insulin resistance and IGF signaling pathways activation and pharmacological control of HCC related to DM were potential targets.
Downloads
References
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nature Reviews. Disease Primers. 2021, 7(1), 6. DOI: 10.1038/s41572-020-00240-3
Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: Implications for screening, prevention and therapy. Nature Reviews. Clinical Oncology. 2023, 20(12), 864-884. DOI: 10.1038/s41571-023-00825-3
Zhang CY, Liu S, Yang M. Hepatocellular carcinoma and obesity, type 2 diabetes mellitus, cardiovascular disease: Causing factors, molecular links, and treatment options. Frontiers in Endocrinology. 2021, 12, 808526. DOI: 10.3389/fendo.2021.808526
Shi TT, Kobara H, Oura K, Masaki T. Mechanisms underlying hepatocellular carcinoma progression in patients with type 2 diabetes. Journal of Hepatocellular Carcinoma. 2021, 8, 45-55. DOI: 10.2147/JHC.S274933
Lin AQ, Xiong MY, Tang BF, Jiang AM, Shen JY, Liu ZQ, et al. Decoding the hepatic fibrosis-hepatocellular carcinoma axis: From mechanisms to therapeutic opportunities. Hepatology International. 2025, 19(4), 732-759. DOI: 10.1007/s12072-025-10838-y
Romeo M, Di Nardo F, Napolitano C, Basile C, Palma C, Vaia P, et al. Exploring the epidemiologic burden, pathogenetic features, and clinical outcomes of primary liver cancer in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: A scoping review. Diabetology. 2025, 6(8), 79. DOI: 10.3390/diabetology6080079
Alqahtani A, Khan Z, Alloghbi A, Said Ahmed TS, Ashraf M, Hammouda DM. Hepatocellular carcinoma: Molecular mechanisms and targeted therapies. Medicina. 2019, 55(9), 526. DOI: 10.3390/medicina55090526.
Jelic MD, Mandic AD, Maricic SM, Srdjenovic BU. Oxidative stress and its role in cancer. Journal of Cancer Research and Therapeutics. 2021, 17(1), 22-28. DOI: 10.4103/jcrt.JCRT_862_16
Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative stress in liver pathophysiology and disease. Antioxidants. 2023, 12(9), 1653. DOI: 10.3390/antiox12091653
Nakamura H, Takada K. Reactive oxygen species in cancer: Current findings and future directions. Cancer Science. 2021, 112(10), 3945-3952. DOI: 10.1111/cas.15068
Fu XT, Qie JB, Chen JF, Gao Z, Li XG, Feng SR, et al. Inhibition of SIRT1 relieves hepatocarcinogenesis via alleviating autophagy and inflammation. International Journal of Biological Macromolecules. 2024, 278, 134120. DOI: 10.1016/j.ijbiomac.2024.134120
Mohan A, Hasan ZW, Galani HG, Afroze T, Niazi RK, Alfaki R, et al. Diabetes and liver cirrhosis: Shared pathways and clinical implications-A narrative review. Annals of Medicine and Surgery. 2025, 87(12), 8418-8425. DOI: 10.1097/MS9.0000000000004012
Black HS. Oxidative stress and ROS link diabetes and cancer. Journal of Molecular Pathology. 2024, 5(1), 96-119. DOI: 10.3390/jmp5010007
Pearson-Stuttard J, Papadimitriou N, Markozannes G, Cividini S, Kakourou A, Gill D, et al. Type 2 diabetes and cancer: An umbrella review of observational and Mendelian randomization studies. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2021, 30(6), 1218-1228. DOI: 10.1158/1055-9965.EPI-20-1245
Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, et al. Mechanisms of hepatocellular carcinoma progression. World Journal of Gastroenterology. 2019, 25(19), 2279-2293. DOI: 10.3748/wjg.v25.i19.2279
Hu YJ, Gao MM, Chenghuang J, Bao R. Insights into the gut-liver axis: Mechanisms and emerging therapies in hepatocellular carcinoma. Frontiers in Pharmacology. 2025, 16, 1595853. DOI: 10.3389/fphar.2025.1595853
Rehman K, Akash MSH, Liaqat A, Kamal S, Qadir MI, Rasul A. Role of interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Critical Reviews™ in Eukaryotic Gene Expression. 2017, 27(3), 229-236. DOI: 10.1615/CritRevEukaryotGeneExpr.2017019712
Liu Y, Hao CH, Li L, Zhang HG, Zha WN, Ma LB, et al. The role of oxidative stress in the development and therapeutic intervention of hepatocellular carcinoma. Current Cancer Drug Targets. 2023, 23(10), 792-804. DOI: 10.2174/1568009623666230418121130
Wallace HL, Russell RS. Inflammatory consequences: Hepatitis C virus-induced inflammasome activation and pyroptosis. Viral Immunology. 2024, 37(3), 126-138. DOI: 10.1089/vim.2023.0138
Yeo YH, Abdelmalek M, Khan S, Moylan CA, Rodriquez L, Villanueva A, et al. Current and emerging strategies for the prevention of hepatocellular carcinoma. Nature Clinical Practice. Gastroenterology & Hepatology. 2025, 22(3), 173-190. DOI: 10.1038/s41575-024-01021-z
Mai YH, Meng LH, Deng GL, Qin YF. The role of type 2 diabetes mellitus-related risk factors and drugs in hepatocellular carcinoma. Journal of Hepatocellular Carcinoma. 2024, 11, 159-171. DOI: 10.2147/JHC.S441672
Liu L, Duan X, Ju BZ. Recent advances in non-alcoholic steatohepatitis-associated hepatocellular carcinoma: Immune cells, metabolic dysregulation, and therapeutic strategies. Frontiers in Oncology. 2026, 15, 1744299. DOI: 10.3389/fonc.2025.1744299
Li ZW, Li YZ, Jiang TQ, Wang Y, Li CJ, He ZY. Quercetin and its metabolites: Mechanistic insights as the basis of their therapeutic potential in NAFLD and HCC. Molecules. 2025, 30(22), 4441. DOI: 10.3390/molecules30224441
Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World Journal of Hepatology. 2017, 9(36), 1305-1314. DOI: 10.4254/wjh.v9.i36.1305.
Kahn A, Barbesino G, Perez J, Xu ZY, Jia XF, Zaman F, et al. Endocrinopathies: Hashimoto thyroiditis, graves disease, hypophysitis, addison disease, premature ovarian failure, male infertility, and diabetes. Manual of Molecular and Clinical Laboratory Immunology. 2024, 2, 987-1013. DOI: 10.1002/9781683674023.ch90
Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of autoimmune hepatitis-Cellular and molecular mechanisms. International Journal of Molecular Sciences. 2021, 22(24), 13578. DOI: 10.3390/ijms222413578
Zhou YM, Tang RQ, Merrill EG, Ma X. Autoimmune hepatitis: pathophysiology. Clinics in Liver Disease. 2024, 28(1), 15-35. DOI: 10.1016/j.cld.2023.06.003
Xu YF, Zhao ZB, Yan EP, Lian ZX, Zhang WC. Complex interplay between the immune system, metabolism, and epigenetic factors in autoimmune liver diseases. Medicine Advances. 2023, 1(2), 97-114. DOI: 10.1002/med4.23
Lammert C, Chalasani SN, Atkinson EJ, McCauley BM, Lazaridis KN. Environmental risk factors are associated with autoimmune hepatitis. Liver International. 2021, 41(10), 2396-2403. DOI: 10.1111/liv.14999
Colapietro F, Maisonneuve P, Lytvyak E, Beuers U, Verdonk RC, Van Der Meer AJ, et al. Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis. Journal of Hepatology. 2024, 80(1), 53-61. DOI: 10.1016/j.jhep.2023.09.010
Huang DQ, Mathurin P, Cortez-Pinto H, Loomba R. Global epidemiology of alcohol-associated cirrhosis and HCC: Trends, projections and risk factors. Nature Reviews. Gastroenterology & Hepatology. 2023, 20(1), 37-49. DOI: 10.1038/s41575-022-00688-6
Kaur KK, Allahbadia GN, Singh M. The association of non-viral liver diseases from NAFLD to NASH to HCC with the pandemic of obesity, type 2 diabetes, or diabesity and metabolic syndrome Etiopathogenetic correlation along with utilization for diagnostic and therapeutic purposes: A systematic review. Journal of Endocrinology Research. 2021, 3(2), 1-24. DOI: 10.30564/jer.v3i2.3520
Vetrano E, Rinaldi L, Mormone A, Giorgione C, Galiero R, Caturano A, et al. Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and non-viral hepatocarcinoma: Pathophysiological mechanisms and new therapeutic strategies. Biomedicines. 2023, 11(2), 468. DOI: 10.3390/biomedicines11020468
Armandi A, Rosso C, Caviglia GP, Bugianesi E. Insulin resistance across the spectrum of nonalcoholic fatty liver disease. Metabolites. 2021, 11(3), 155. DOI: 10.3390/metabo11030155
Rigopoulou EI, Dalekos GN. Current trends and characteristics of hepatocellular carcinoma in patients with autoimmune liver diseases. Cancers. 2021, 13(5), 1023. DOI: 10.3390/cancers13051023
Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clinical and Molecular Hepatology. 2023, 29(1), 51-64. DOI: 10.3350/cmh.2022.0095
Ma-On C, Sanpavat A, Whongsiri P, Suwannasin S, Hirankarn N, Tangkijvanich P, et al. Oxidative stress indicated by elevated expression of Nrf2 and 8-OHdG promotes hepatocellular carcinoma progression. Medical Oncology. 2017, 34(4), 57. DOI: 10.1007/s12032-017-0914-5
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine. 2001, 7(8), 941-946. DOI: 10.1038/90984
Nakamura T, Masuda A, Nakano D, Amano K, Sano T, Nakano M, et al. Pathogenic mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD)-associated hepatocellular carcinoma. Cells. 2025, 14(6), 428. DOI: 10.3390/cells14060428
Reeves HL, Zaki MY, Day CP. Hepatocellular carcinoma in obesity, type 2 diabetes, and NAFLD. Digestive Diseases and Sciences. 2016, 61(5), 1234-1245. DOI: 10.1007/s10620-016-4085-6.
Nahon P, Allaire M, Nault JC, Paradis V. Characterizing the mechanism behind the progression of NAFLD to hepatocellular carcinoma. Hepatic Oncology. 2020, 7(4), HEP36. DOI: 10.2217/hep-2020-0017
Malik A, Thanekar U, Amarachintha S, Mourya R, Nalluri S, Bondoc A, et al. “Complimenting the complement”: Mechanistic insights and opportunities for therapeutics in hepatocellular carcinoma. Frontiers in Oncology. 2021, 10, 627701. DOI: 10.3389/fonc.2020.627701
Manilla V, Santopaolo F, Gasbarrini A, Ponziani FR. Type 2 diabetes mellitus and liver disease: Across the gut-liver axis from fibrosis to cancer. Nutrients. 2023, 15(11), 2521. DOI: 10.3390/nu15112521
Gan L, Wang W, Jiang JX, Tian K, Liu W, Cao ZM. Dual role of Nrf2 signaling in hepatocellular carcinoma: Promoting development, immune evasion, and therapeutic challenges. Frontiers in Immunology. 2024, 15, 1429836. DOI: 10.3389/fimmu.2024.1429836
Chatzikalil E, Arvanitakis K, Kalopitas G, Florentin M, Germanidis G, Koufakis T, et al. Hepatic iron overload and hepatocellular carcinoma: New insights into pathophysiological mechanisms and therapeutic approaches. Cancers. 2025, 17(3), 392. DOI: 10.3390/cancers17030392
Takakura K, Oikawa T, Nakano M, Saeki C, Torisu Y, Kajihara M, et al. Recent insights into the multiple pathways driving non-alcoholic steatohepatitis-derived hepatocellular carcinoma. Frontiers in Oncology. 2019, 9, 762. DOI: 10.3389/fonc.2019.00762
Wen YK, Ma LC, Ju C. Recent insights into the pathogenesis and therapeutic targets of chronic liver diseases. eGastroenterology. 2023, 1(2), e100020. DOI: 10.1136/ egastro-2023-100020
Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK. From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence. Liver Cancer. 2013, 2(3-4), 367-383. DOI: 10.1159/000343852
Gnocchi D, Sabbà C, Massimi M, Mazzocca A. Metabolism as a new avenue for hepatocellular carcinoma therapy. International Journal of Molecular Sciences. 2023, 24(4), 3710. DOI: 10.3390/ijms24043710
Rorsman P, Ashcroft FM. Pancreatic β-cell electrical activity and insulin secretion: Of mice and men. Physiological Reviews. 2018, 98(1), 117-214. DOI: 10.1152/physrev.00008.2017
Chen PG, Li YX, Dai YY, Wang ZM, Zhou YP, Wang Y, et al. Advances in the pathogenesis of metabolic liver disease-related hepatocellular carcinoma. Journal of Hepatocellular Carcinoma. 2024, 11, 581-594. DOI: 10.2147/JHC.S450460
Ma L, Wang H, Jin QY, Sun ZW, Yu S, Zhang Y. The gut-liver axis: Molecular mechanisms and therapeutic targeting in liver disease. International Journal of General Medicine. 2025, 18, 7531-7546. DOI: 10.2147/IJGM.S551494
Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, et al. Role of non-coding RNAs in hepatocellular carcinoma progression: From classic to novel clinicopathogenetic implications. Cancers. 2023, 15(21), 5178. DOI: 10.3390/cancers15215178
Mejía-Guzmán JE, Belmont-Hernández RA, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Metabolic-dysfunction-associated steatotic liver disease: Molecular mechanisms, clinical implications, and emerging therapeutic strategies. International Journal of Molecular Sciences. 2025, 26(7), 2959. DOI: 10.3390/ijms26072959
Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-faced role of autophagy in hepatocellular carcinoma: Implications for therapeutic interventions. International Journal of Molecular Sciences. 2023, 24(22), 16255. DOI: 10.3390/ijms242216255
Wang XB, Zhang L, Dong BN. Molecular mechanisms in MASLD/MASH-related HCC. Hepatology. 2025, 82(5), 1303-1324. DOI: 10.1097/HEP.0000000000000786
Asiri A, Al Qarni A, Bakillah A. The interlinking metabolic association between type 2 diabetes mellitus and cancer: Molecular mechanisms and therapeutic insights. Diagnostics. 2024, 14(19), 2132. DOI: 10.3390/diagnostics14192132
Hashemi M, Nadafzadeh N, Imani MH, Rajabi R, Ziaolhagh S, Bayanzadeh SD, et al. Targeting and regulation of autophagy in hepatocellular carcinoma: Revisiting the molecular interactions and mechanisms for new therapy approaches. Cell Communication and Signaling. 2023, 21(1), 32. DOI: 10.1186/s12964-023-01053-z
Gizak A, Duda P, Wisniewski J, Rakus D. Fructose-1,6-bisphosphatase: From a glucose metabolism enzyme to multifaceted regulator of a cell fate. Advances in Biological Regulation. 2019, 72, 41-50. DOI: 10.1016/j.jbior.2019.03.001
Peiseler M, Tacke F. Inflammatory mechanisms underlying nonalcoholic steatohepatitis and the transition to hepatocellular carcinoma. Cancers. 2021, 13(4), 730. DOI: 10.3390/cancers13040730
Bian XL, Chen HZ, Yang PB, Li YP, Zhang FN, Zhang JY, et al. Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation. Nature Communications. 2017, 8, 14420. DOI: 10.1038/ncomms14420
Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World Journal of Gastroenterology. 2022, 28(21), 2251-2281. DOI: 10.3748/wjg.v28.i21.2251
Kounatidis D, Vallianou NG, Karampela I, Rebelos E, Kouveletsou M, Dalopoulos V, et al. Anti-diabetic therapies and cancer: From bench to bedside. Biomolecules. 2024, 14(11), 1479. DOI: 10.3390/biom14111479
Jin Y, Alissa M, Ahmed AE, Al-Doaiss AA, Asiri N, Assiri Y, et al. The triadic relationship between nonalcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease: From molecular mechanisms to clinical management. Current Problems in Cardiology. 2025, 50(11), 103170. DOI: 10.1016/j.cpcardiol.2025.103170
Ghafoor N, Mehar T, Batool M, Salar MZ, Ahmed MZ, Atique U. Attenuative effects of poncirin against polyethylene microplastics-prompted hepatotoxicity in rats. Journal of King Saud University Science. 2024, 36, 103475. DOI: 10.1016/j.jksus.2024.103475
Tian ZL, Xu C, Yang PJ, Lin ZB, Wu WL, Zhang WJ, et al. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Frontiers in Immunology. 2022, 13, 984728. DOI: 10.3389/fimmu.2022.984728
Xi J, Lei S, Chen J, Liu J, Shan C, Sun X, et al. Killing hepatocellular carcinoma in the NAFLD/NASH stage: A comprehensive perspective on targeting regulated cell death. Cell Death Discovery. 2025, 11(1), 281. DOI: 10.1038/s41420-025-02558-x
Wang N, Guo M, Zhang C, Jiang R, Bi J, Sun J, et al. Liver regeneration: Unraveling the molecular mechanisms and clinical application. Journal of Translational Medicine. 2025, 23(1), 1409. DOI: 10.1186/s12967-025-07412-3
Papadakos SP, Arvanitakis K, Stergiou IE, Vallilas C, Sougioultzis S, Germanidis G, et al. Interplay of extracellular vesicles and TLR4 signaling in hepatocellular carcinoma pathophysiology and therapeutics. Pharmaceutics. 2023, 15(10), 2460. DOI: 10.3390/pharmaceutics15102460
Yu HQ, Ding HF, Huang Y, Cao HZ, Ding Y, Wang WL. From HBV to MASLD cirrhosis: Mechanistic insights and therapeutic strategies. Portal Hypertension & Cirrhosis. 2026, 1-19. DOI: 10.1002/poh2.70036
An LB, Li ZF. Molecular network of metabolic reprogramming and precision diagnosis and treatment of hepatocellular carcinoma. Biomarker Research. 2025, 13(1), 124. DOI: 10.1186/s40364-025-00844-5
Song Y, Lau HC, Zhang X, Yu J. Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma. Cancer Biology & Medicine. 2023, 21(2), 144-162. DOI: 10.20892/j.issn.2095-3941.2023.0394
Truong XT, Lee DH. Hepatic insulin resistance and steatosis in metabolic dysfunction-associated steatotic liver disease: New insights into mechanisms and clinical implications. Diabetes & Metabolism Journal. 2025, 49(5), 964-986. DOI: 10.4093/dmj.2025.0644
Pei Q, Yi Q, Tang L. Liver fibrosis resolution: From molecular mechanisms to therapeutic opportunities. International Journal of Molecular Sciences. 2023, 24(11), 9671. DOI: 10.3390/ijms24119671
Jiang LL, Meng Q, Liu LX, Li WH. A comprehensive review on molecular mechanisms, treatments, and brief role of natural products in hepatocellular cancer. Natural Product Communications. 2024, 19(9). DOI: 10.1177/1934578X24128487
Zeng L, Zhu L, Fu S, Li Y, Hu K. Mitochondrial dysfunction: Molecular mechanisms and potential treatment approaches of hepatocellular carcinoma. Molecular and Cellular Biochemistry. 2025, 480(4), 2131-2142. DOI: 10.1007/s11010-024-05144-4
Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, et al. Glucagon-like peptide-1 receptor agonists and cancer risk: Advancing precision medicine through mechanistic understanding and clinical evidence. Biomarker Research. 2025, 13(1), 50. DOI: 10.1186/s40364-025-00765-3
Yadav S, Kumar R. Gut microbiota and the gut-liver axis in hepatocellular carcinoma: A comprehensive review of pathogenesis and therapeutic strategies. Anti-cancer Agents in Medicinal Chemistry. 2025, 25(17), 1287-1301. DOI: 10.2174/0118715206364200250304034753
Lu X, Xu S, Deng Z, Wang MJ, Chen F. Molecular mechanisms and genetic features of cholangiocarcinoma: Implications for targeted therapeutic strategies. Precision Clinical Medicine. 2025, 8(3), 21. DOI: 10.1093/pcmedi/pbaf021
Ngo MT, Jeng HY, Kuo YC, Diony Nanda J, Brahmadhi A, Ling TY, et al. The role of IGF/IGF-1R signaling in hepatocellular carcinomas: Stemness-related properties and drug resistance. International Journal of Molecular Sciences. 2021, 22(4), 1931. DOI: 10.3390/ijms22041931
Zhu YW, Cai BS. Mechanisms and therapeutic insights into MASH-associated fibrosis. Trends in Endocrinology and Metabolism: TEM. 2026, 37(5), 402-417. DOI: 10.1016/j.tem.2025.09.004
Boissan M, Beurel E, Wendum D, Rey C, Lécluse Y, Housset C, et al. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. The American Journal of Pathology. 2005, 167(3), 869-877. DOI: 10.1016/S0002-9440(10)62058-5
Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochemical Pharmacology. 2004, 68(6), 1003-15. DOI: 10.1016/j.bcp.2004.05.029
Luo X, Cao M, Gao F, He X. YTHDF1 promotes hepatocellular carcinoma progression via activating PI3K/AKT/mTOR signaling pathway and inducing epithelial-mesenchymal transition. Experimental Hematology & Oncology. 2021, 10(1), 35. DOI: 10.1186/s40164-021-00227-0
Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: An emphasis on molecular pathways. Journal of Hepatocellular Carcinoma. 2021, 8, 1415-1444. DOI: 10.2147/JHC.S336858
Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World Journal of Gastroenterology. 2016, 22(2), 823-832. DOI: 10.3748/wjg.v22.i2.823
Ghafoor N, Ehsan N. Renoprotective potential of robustaflavone against diabetes induced kidney damage via regulating oxidative stress, inflammation and apoptosis. Pakistan Veterinary Journal. 2026, 46(3), 719-725. DOI: 10.29261/pakvetj/2026.061
Lee YH. Therapeutic targeting alternative splicing to inhibit hepatocellular carcinoma metastasis. Translational Cancer Research. 2022, 11(11), 3929-3931. DOI: 10.21037/tcr-22-2207
Cui H, Guo D, Zhang X, Zhu Y, Wang Z, Jin Y, et al. ENO3 inhibits growth and metastasis of hepatocellular carcinoma via Wnt/β-catenin signaling pathway. Frontiers in Cell and Developmental Biology. 2021, 9, 797102. DOI: 10.3389/fcell.2021.797102
Vallée A, Lecarpentier Y. Crosstalk between peroxisome proliferator-activated receptor gamma and the canonical WNT/β-catenin pathway in chronic inflammation and oxidative stress during carcinogenesis. Frontiers in Immunology. 2018, 9, 745. DOI: 10.3389/fimmu.2018.00745
Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver International. 2018, 38(11), 2018-2027. DOI: 10.1111/liv.13872
Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: A systematic review and meta-analysis. The Oncologist. 2013, 18(12), 1248-55. DOI: 10.1634/theoncologist.2013-0111
Singh MK, Das BK, Choudhary S, Gupta D, Patil UK. Diabetes and hepatocellular carcinoma: A pathophysiological link and pharmacological management. Biomedicine & Pharmacotherapy. 2018, 106, 991-1002. DOI: 10.1016/j.biopha.2018.06.095
Guo Y, Xiao Z, Yang L, Gao Y, Zhu Q, Hu L, et al. Hypoxia inducible factors in hepatocellular carcinoma (Review). Oncology Reports. 2020, 43(1), 3-15. DOI: 10.3892/or.2019.7397
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. The New England Journal of Medicine. 2020, 382(20), 1894-1905. DOI: 10.1056/NEJMoa1915745
Mu W, Cheng X, Zhang X, Liu Y, Lv Q, Liu G, et al. Hinokiflavone induces apoptosis via activating mitochondrial ROS/JNK/caspase pathway and inhibiting NF-κB activity in hepatocellular carcinoma. Journal of Cellular and Molecular Medicine. 2020, 24(14), 8151-8165. DOI: 10.1111/jcmm.15474
Lluch P, Segarra G, Tosca J, Navarro L, Navarrete-Navarro J, Herrera G, et al. Oxidative and nitrosative pattern in circulating leukocytes of very early/early hepatocellular carcinoma patients. Anticancer Research. 2020, 40(12), 6853-6861. DOI: 10.21873/anticanres.14707
Zhan X, Wu R, Kong XH, You Y, He K, Sun XY, et al. Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitates the growth and metastasis of hepatocellular carcinoma. Cancer Communications. 2023, 43(2), 225-245. DOI: 10.1002/cac2.12388
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Chaman Ara, Fazeela Zaka, Asma Batool, Sajal Hafza Khan, Noor ul Huda Zafar
This work is licensed under a Creative Commons Attribution 4.0 International License.
