Mitochondrial gatekeeper in hepatocellular carcinoma: Unraveling the multifaceted roles of VDAC in metabolic reprogramming, apoptosis evasion and therapeutic innovation (Review)

Chavez-Tapia NC, Murúa-Beltrán Gall S, Ordoñez-Vázquez AL, Nuño-Lambarri N, Vidal-Cevallos P and Uribe M: Understanding the role of metabolic syndrome as a risk factor for hepatocellular carcinoma. J Hepatocell Carcinoma. 9:583–593. 2022. View Article : Google Scholar

Jia G, He P, Dai T, Goh D, Wang J, Sun M, Wee F, Li F, Lim JCT, Hao S, et al: Spatial immune scoring system predicts hepatocellular carcinoma recurrence. Nature. 640:1031–1041. 2025. View Article : Google Scholar : PubMed/NCBI

Huang Q, Wu D, Zhao J, Yan Z, Chen L, Guo S, Wang D, Yuan C, Wang Y, Liu X and Xing J: TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis. EMBO J. 41:e1103242022. View Article : Google Scholar : PubMed/NCBI

Zheng Y, Shi Y, Tian C, Jiang C, Jin H, Chen J, Almasan A, Tang H and Chen Q: Essential role of the voltage-dependent anion channel (VDAC) in mitochondrial permeability transition pore opening and cytochrome c release induced by arsenic trioxide. Oncogene. 23:1239–1247. 2004. View Article : Google Scholar : PubMed/NCBI

Su Y, Luo Y, Zhang P, Lin H, Pu W, Zhang H, Wang H, Hao Y, Xiao Y, Zhang X, et al: Glucose-induced CRL4(COP1)-p53 axis amplifies glycometabolism to drive tumorigenesis. Mol Cell. 83:2316–2331.e7. 2023. View Article : Google Scholar

Wang TS, Coppens I, Saorin A, Brady NR and Hamacher-Brady A: Endolysosomal targeting of mitochondria is integral to BAX-mediated mitochondrial permeabilization during apoptosis signaling. Dev Cell. 53:627–645.e7. 2020. View Article : Google Scholar

Liu J, Huang B, Xiu Z, Zhou Z, Liu J, Li X and Tang X: PI3K/Akt/HIF-1α signaling pathway mediates HPV-16 oncoprotein-induced expression of EMT-related transcription factors in non-small cell lung cancer cells. J Cancer. 9:3456–3466. 2018. View Article : Google Scholar : PubMed/NCBI

Heslop KA, Milesi V and Maldonado EN: VDAC modulation of cancer metabolism: Advances and therapeutic challenges. Front Physiol. 12:7428392021. View Article : Google Scholar

Li Y, Yan H, Xu X, Liu H, Wu C and Zhao L: Erastin/sorafenib induces cisplatin-resistant non-small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway. Oncol Lett. 19:323–333. 2020.

Fang D and Maldonado EN: VDAC regulation: A mitochondrial target to stop cell proliferation. Adv Cancer Res. 138:41–69. 2018. View Article : Google Scholar : PubMed/NCBI

Yuan S, Sun R, Shi H, Chapman NM, Hu H, Guy C, Rankin S, Kc A, Palacios G, Meng X, et al: VDAC2 loss elicits tumour destruction and inflammation for cancer therapy. Nature. 640:1062–1071. 2025. View Article : Google Scholar : PubMed/NCBI

Fang Y, Liu J, Zhang Q, She C, Zheng R, Zhang R, Chen Z, Chen C and Wu J: Overexpressed VDAC1 in breast cancer as a novel prognostic biomarker and correlates with immune infiltrates. World J Surg Oncol. 20:2112022. View Article : Google Scholar

Pittala S, Krelin Y and Shoshan-Barmatz V: Targeting liver cancer and associated pathologies in mice with a mitochondrial VDAC1-Based Peptide. Neoplasia. 20:594–609. 2018. View Article : Google Scholar

Liu C, Li HJ, Duan WX, Duan Y, Yu Q, Zhang T, Sun YP, Li YY, Liu YS and Xu SC: MCU upregulation overactivates mitophagy by promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium. Adv Sci (Weinh). 10:e22038692023. View Article : Google Scholar : PubMed/NCBI

Yang C, Zhao Y, Wang L, Guo Z, Ma L, Yang R, Wu Y, Li X, Niu J, Chu Q, et al: De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence. Nat Cell Biol. 25:836–847. 2023. View Article : Google Scholar

Mahmoud AM, Kostrzewa M, Marolda V, Cerasuolo M, Maccarinelli F, Coltrini D, Rezzola S, Giacomini A, Mollica MP, Motta A, et al: Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer. Pharmacol Res. 189:1066832023. View Article : Google Scholar : PubMed/NCBI

Chin HS, Li MX, Tan IKL, Ninnis RL, Reljic B, Scicluna K, Dagley LF, Sandow JJ, Kelly GL, Samson AL, et al: VDAC2 enables BAX to mediate apoptosis and limit tumor development. Nat Commun. 9:49762018. View Article : Google Scholar : PubMed/NCBI

Turcios L, Marti F, Watt DS, Kril LM, Khurana A, Chapelin F, Liu C, Zwischenberger JB, Evers BM and Gedaly R: Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma. Oncotarget. 11:3013–3024. 2020. View Article : Google Scholar

Grills C, Jithesh PV, Blayney J, Zhang SD and Fennell DA: Gene expression meta-analysis identifies VDAC1 as a predictor of poor outcome in early stage non-small cell lung cancer. PLoS One. 6:e146352011. View Article : Google Scholar : PubMed/NCBI

Xing T, Li L, Chen Y, Ju G, Li G, Zhu X, Ren Y, Zhao J, Cheng Z, Li Y, et al: Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma. Cell Rep Med. 4:1012642023. View Article : Google Scholar : PubMed/NCBI

Ren X, Zhou H, Sun Y, Fu H, Ran Y, Yang B, Yang F, Bjorklund M and Xu S: MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans. EMBO Rep. 24:e562972023. View Article : Google Scholar : PubMed/NCBI

Conti Nibali S, De Siervi S, Luchinat E, Magrì A, Messina A, Brocca L, Mantovani S, Oliviero B, Ahmed MH, Mondelli MU, et al: VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference. iScience. 27:1098532024. View Article : Google Scholar

Luo P, Zhang Q, Shen S, An Y, Yuan L, Wong YK, Huang S, Huang S, Huang J, Cheng G, et al: Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma. Asian J Pharm Sci. 18:1008742023. View Article : Google Scholar

Yuan Z, Dewson G, Czabotar PE and Birkinshaw RW: VDAC2 and the BCL-2 family of proteins. Biochem Soc Trans. 49:2787–2795. 2021. View Article : Google Scholar : PubMed/NCBI

Zerbib E, Arif T, Shteinfer-Kuzmine A, Chalifa-Caspi V and Shoshan-Barmatz V: VDAC1 silencing in cancer cells leads to metabolic reprogramming that modulates tumor microenvironment. Cancers (Basel). 13:28502021. View Article : Google Scholar : PubMed/NCBI

Nong S, Han X, Xiang Y, Qian Y, Wei Y, Zhang T, Tian K, Shen K, Yang J and Ma X: Metabolic reprogramming in cancer: Mechanisms and therapeutics. MedComm (2020). 4:e2182023. View Article : Google Scholar : PubMed/NCBI

Gershon TR, Crowther AJ, Tikunov A, Garcia I, Annis R, Yuan H, Miller CR, Macdonald J, Olson J and Deshmukh M: Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab. 1:22013. View Article : Google Scholar : PubMed/NCBI

Ciscato F, Ferrone L, Masgras I, Laquatra C and Rasola A: Hexokinase 2 in cancer: A prima donna playing multiple characters. Int J Mol Sci. 22:47162021. View Article : Google Scholar

Maldonado EN: VDAC-Tubulin, an anti-warburg pro-oxidant switch. Front Oncol. 7:42017. View Article : Google Scholar

Heslop KA, Burger P, Kappler C, Solanki AK, Gooz M, Peterson YK, Mills C, Benton T, Duncan SA, Woster PM and Maldonado EN: Small molecules targeting the NADH-binding pocket of VDAC modulate mitochondrial metabolism in hepatocarcinoma cells. Biomed Pharmacother. 150:1129282022. View Article : Google Scholar : PubMed/NCBI

He Z, Zhang J, Xu Y, Fine EJ, Suomivuori CM, Dror RO and Feng L: Structure of mitochondrial pyruvate carrier and its inhibition mechanism. Nature. 641:250–257. 2025. View Article : Google Scholar : PubMed/NCBI

Chen L, Lin X, Lei Y, Xu X, Zhou Q, Chen Y, Liu H, Jiang J, Yang Y, Zheng F and Wu B: Aerobic glycolysis enhances HBx-initiated hepatocellular carcinogenesis via NF-κBp65/HK2 signalling. J Exp Clin Cancer Res. 41:3292022. View Article : Google Scholar : PubMed/NCBI

Zhang Y, Li W, Bian Y, Li Y and Cong L: Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma. PeerJ. 11:e147972023. View Article : Google Scholar : PubMed/NCBI

Rostovtseva TK, Bezrukov SM and Hoogerheide DP: Regulation of mitochondrial respiration by VDAC Is enhanced by membrane-bound inhibitors with disordered polyanionic C-terminal domains. Int J Mol Sci. 22:73582021. View Article : Google Scholar

Ning Z, Guo X, Liu X, Lu C, Wang A, Wang X, Wang W, Chen H, Qin W, Liu X, et al: USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma. Nat Commun. 13:21872022. View Article : Google Scholar : PubMed/NCBI

Varughese JT, Buchanan SK and Pitt AS: The role of voltage-dependent anion channel in mitochondrial dysfunction and human disease. Cells. 10:17372021. View Article : Google Scholar : PubMed/NCBI

Yang J, Lu X, Hao JL, Li L, Ruan YT, An XN, Huang QL, Dong XM and Gao P: VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis. Nat Commun. 16:11602025. View Article : Google Scholar : PubMed/NCBI

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, et al: Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 169:132–147.e16. 2017. View Article : Google Scholar

Tomasello F, Messina A, Lartigue L, Schembri L, Medina C, Reina S, Thoraval D, Crouzet M, Ichas F, De Pinto V and De Giorgi F: Outer membrane VDAC1 controls permeability transition of the inner mitochondrial membrane in cellulo during stress-induced apoptosis. Cell Res. 19:1363–1376. 2009. View Article : Google Scholar : PubMed/NCBI

Shoshan-Barmatz V, Shteinfer-Kuzmine A and Verma A: VDAC1 at the intersection of cell metabolism, apoptosis, and diseases. Biomolecules. 10:14852020. View Article : Google Scholar : PubMed/NCBI

Ding L, Wu JP, Xu G, Zhu B, Zeng QM, Li DF and Lu W: Lentiviral-mediated RNAi targeting caspase-3 inhibits apoptosis induced by serum deprivation in rat endplate chondrocytes in vitro. Braz J Med Biol Res. 47:445–451. 2014. View Article : Google Scholar : PubMed/NCBI

Moldoveanu T: Apoptotic mitochondrial poration by a growing list of pore-forming BCL-2 family proteins. Bioessays. 45:e22002212023. View Article : Google Scholar : PubMed/NCBI

Zhang X, Zhang X, Ren J, Li J, Wei X, Yu Y, Yi Z and Wei W: Precise modelling of mitochondrial diseases using optimized mitoBEs. Nature. 639:735–745. 2025. View Article : Google Scholar : PubMed/NCBI

Garcia S, Saldana-Caboverde A, Anwar M, Raval AP, Nissanka N, Pinto M, Moraes CT and Diaz F: Enhanced glycolysis and GSK3 inactivation promote brain metabolic adaptations following neuronal mitochondrial stress. Hum Mol Genet. 31:692–704. 2022. View Article : Google Scholar

Qiu XY, Hu DX, Chen WQ, Chen RQ, Qian SR, Li CY, Li YJ, Xiong XX, Liu D, Pan F, et al: PD-L1 confers glioblastoma multiforme malignancy via Ras binding and Ras/Erk/EMT activation. Biochim Biophys Acta Mol Basis Dis. 1864((5 Pt A)): 1754–1769. 2018. View Article : Google Scholar : PubMed/NCBI

Yao H, Lan J, Li C, Shi H, Brosseau JP, Wang H, Lu H, Fang C, Zhang Y, Liang L, et al: Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng. 3:306–317. 2019. View Article : Google Scholar : PubMed/NCBI

Shen YG, Ji MM, Yi HM, Shen R, Fu D, Cheng S, Huang CX, Wang L, Xu PP, Dou HJ and Zhao WL: CD47 overexpression is related to tumour-associated macrophage infiltration and diffuse large B-cell lymphoma progression. Clin Transl Med. 14:e15322024. View Article : Google Scholar : PubMed/NCBI

Shi Y, Huang G, Jiang F, Zhu J, Xu Q, Fang H, Lan S, Pan Z, Jian H, Li L and Zhang Y: Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma. Front Immunol. 13:10705932022. View Article : Google Scholar

Zhang K, Yuan B, Dai X, Chen W, Zhang C, Qiao Y, Cao W, Chen Y, Duan X, Zhang X, et al: Selection and identification of DNA aptamer binding VDAC1 for tumor tissue imaging and targeted drug delivery. Int J Biol Macromol. 306((Pt 1)): 1412492025. View Article : Google Scholar

Ko JH, Gu W, Lim I, Zhou T and Bang H: Expression profiling of mitochondrial voltage-dependent anion channel-1 associated genes predicts recurrence-free survival in human carcinomas. PLoS One. 9:e1100942014. View Article : Google Scholar : PubMed/NCBI

Ma Y, Han B, Yu Q, Zha N, Deng Z, Liang J and Yu R: Single-cell and bulk RNA sequencing data jointly reveals VDAC2′s impacts on prognosis and immune landscape of NSCLC. Aging (Albany NY). 16:3160–3184. 2024. View Article : Google Scholar : PubMed/NCBI

Chen S, Ning B, Song J, Yang Z, Zhou L, Chen Z, Mao L, Liu H, Wang Q, He S and Zhou Z: Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis. Int J Biol Sci. 18:2304–2316. 2022. View Article : Google Scholar

Karmi O, Marjault HB, Bai F, Roy S, Sohn YS, Darash Yahana M, Morcos F, Ioannidis K, Nahmias Y, Jennings PA, et al: A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics. Proc Natl Acad Sci USA. 119:e21214911192022. View Article : Google Scholar : PubMed/NCBI

Arif T, Paul A, Krelin Y, Shteinfer-Kuzmine A and Shoshan-Barmatz V: Mitochondrial VDAC1 silencing leads to metabolic rewiring and the reprogramming of tumour cells into advanced differentiated states. Cancers (Basel). 10:4992018. View Article : Google Scholar : PubMed/NCBI

Cervantes-Silva MP, Cox SL and Curtis AM: Alterations in mitochondrial morphology as a key driver of immunity and host defence. EMBO Rep. 22:e530862021. View Article : Google Scholar : PubMed/NCBI

Zhang L, Zhang X, Liu H, Yang C, Yu J, Zhao W, Guo J, Zhou B and Jiang N: MTFR2-dependent mitochondrial fission promotes HCC progression. J Transl Med. 22:732024. View Article : Google Scholar : PubMed/NCBI

Qu M, Zhang G, Qu H, Vu A, Wu R, Tsukamoto H, Jia Z, Huang W, Lenz HJ, Rich JN and Kay SA: Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle. Proc Natl Acad Sci USA. 120:e22148291202023. View Article : Google Scholar : PubMed/NCBI

Pan X, Zhao Y, Li Y, Chen J, Zhang W, Yang L, Xiong YZ, Ying Y, Xu H, Zhang Y, et al: Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance. Nat Commun. 15:106812024. View Article : Google Scholar : PubMed/NCBI

Medeiros HCD and Lunt SY: The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation. Mol Cell. 82:3119–3121. 2022. View Article : Google Scholar

Vijayan M, Alvir RV, Alvir RV, Bunquin LE, Pradeepkiran JA and Reddy PH: A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model. Aging Cell. 21:e136632022. View Article : Google Scholar

Amsalem Z, Arif T, Shteinfer-Kuzmine A, Chalifa-Caspi V and Shoshan-Barmatz V: The mitochondrial protein VDAC1 at the crossroads of cancer cell metabolism: The epigenetic link. Cancers (Basel). 12:10312020. View Article : Google Scholar : PubMed/NCBI

Shen S, Dean DC, Yu Z and Duan Z: Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway. Hepatol Res. 49:1097–1108. 2019. View Article : Google Scholar : PubMed/NCBI

Tian LY, Smit DJ and Jücker M: The Role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism. Int J Mol Sci. 24:26522023. View Article : Google Scholar

Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB and Hay N: Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15:1406–1418. 2001. View Article : Google Scholar : PubMed/NCBI

Zhang W, Tang Y, Yang P, Chen Y, Xu Z, Qi C, Huang H, Liu R, Qin H, Ke H, et al: TMX2 potentiates cell viability of hepatocellular carcinoma by promoting autophagy and mitophagy. Autophagy. 20:2146–2163. 2024. View Article : Google Scholar : PubMed/NCBI

Xie X, Shu R, Yu C, Fu Z and Li Z: Mammalian AKT, the emerging roles on mitochondrial function in diseases. Aging Dis. 13:157–174. 2022. View Article : Google Scholar : PubMed/NCBI

Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A and Sethi G: Wnt/β-catenin signaling as a driver of hepatocellular carcinoma progression: An emphasis on molecular pathways. J Hepatocell Carcinoma. 8:1415–1444. 2021. View Article : Google Scholar

Liang Y, Mei Q, He E, Ballar P, Wei C, Wang Y, Dong Y, Zhou J, Tao X, Qu W, et al: MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/β-catenin signaling. Cell Death Dis. 15:6812024. View Article : Google Scholar : PubMed/NCBI

Hwang WY, Kostiuk V, González DP, Lusk CP and Khokha MK: Kap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling. Elife. 11:e704952022. View Article : Google Scholar : PubMed/NCBI

Guo Q, Kim A, Li B, Ransick A, Bugacov H, Chen X, Lindström N, Brown A, Oxburgh L, Ren B and McMahon AP: A beta-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells. Elife. 10:e644442021. View Article : Google Scholar : PubMed/NCBI

Zhao Z, Cui T, Wei F, Zhou Z, Sun Y, Gao C, Xu X and Zhang H: Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: pathogenic role and therapeutic target. Front Oncol. 14:13673642024. View Article : Google Scholar

Moon H and Ro SW: MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel). 13:30262021. View Article : Google Scholar : PubMed/NCBI

Hacohen Lev-Ran A and Seger R: Retention of ERK in the cytoplasm mediates the pluripotency of embryonic stem cells. Stem Cell Reports. 18:305–318. 2023. View Article : Google Scholar : PubMed/NCBI

Bhattacharya R, Ray Chaudhuri S and Roy SS: FGF9-induced ovarian cancer cell invasion involves VEGF-A/VEGFR2 augmentation by virtue of ETS1 upregulation and metabolic reprogramming. J Cell Biochem. 119:8174–8189. 2018. View Article : Google Scholar : PubMed/NCBI

Lang L, Loveless R, Dou J, Lam T, Chen A, Wang F, Sun L, Juarez J, Qin ZS, Saba NF, et al: ATAD3A mediates activation of RAS-independent mitochondrial ERK1/2 signaling, favoring head and neck cancer development. J Exp Clin Cancer Res. 41:432022. View Article : Google Scholar : PubMed/NCBI

Nian Z, Dou Y, Shen Y, Liu J, Du X, Jiang Y, Zhou Y, Fu B, Sun R, Zheng X, et al: Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation. Immunity. 57:2344–2361.e7. 2024. View Article : Google Scholar : PubMed/NCBI

Shen J, Wang Q, Mao Y, Gao W and Duan S: Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies. MedComm (2020). 4:e2882023. View Article : Google Scholar : PubMed/NCBI

Zhou Y, Cui G, Xu H, Chun J, Yang D, Zhang Z, Yang L, Wang J, Wan M, Calvisi DF, et al: Loss of TP53 cooperates with c-MET overexpression to drive hepatocarcinogenesis. Cell Death Dis. 14:4762023. View Article : Google Scholar : PubMed/NCBI

Chen C, Du Y, Nie R, Wang S, Wang H and Li P: Notch signaling in cancers: mechanism and potential therapy. Front Cell Dev Biol. 13:15429672025. View Article : Google Scholar

Hou SS, Ikegawa Y, Kwon Y, Wieckiewicz N, Houser MCQ, Lundin B, Bacskai BJ, Berezovska O and Maesako M: Recording gamma-secretase activity in living mouse brains. ELife. 13:RP968482024. View Article : Google Scholar : PubMed/NCBI

Townson JM, Gomez-Lamarca MJ, Santa Cruz Mateos C and Bray SJ: OptIC-Notch reveals mechanism that regulates receptor interactions with CSL. Development. 150:dev2017852023.

Wang X, Guo Y, Lin P, Yu M, Song S, Xu W, Kong D, Wang Y, Zhang Y, Lu F, et al: Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways. EMBO J. 43:6336–6363. 2024. View Article : Google Scholar : PubMed/NCBI

Kumari L, Mishra L, Sharma Y, Chahar K, Kumar M, Patel P, Gupta GD and Kurmi BD: NOTCH signaling pathway: Occurrence, mechanism, and NOTCH-directed therapy for the management of cancer. Cancer Biother Radiopharm. 39:19–34. 2024. View Article : Google Scholar : PubMed/NCBI

Huang D, Xu M, Wang H, Zhao Y, Zhang Z, Yu M, Zhou M, Pan J, Zeng H, Yu Z, et al: SIRPα blockade therapy potentiates immunotherapy by inhibiting PD-L1(+) myeloid cells in hepatocellular carcinoma. Cell Death Dis. 16:4512025. View Article : Google Scholar : PubMed/NCBI

Ding WZ, Han GY, Jin HH, Zhan CF, Ji Y and Huang XL: Anti-IL-20 monoclonal antibody suppresses hepatocellular carcinoma progression. Oncol Lett. 16:6156–6162. 2018.

Kinsey E and Lee HM: Management of hepatocellular carcinoma in 2024: The multidisciplinary paradigm in an evolving treatment landscape. Cancers (Basel). 16:6662024. View Article : Google Scholar : PubMed/NCBI

Zhu X, Luo L, Xiong Y, Jiang N, Wang Y, Lv Y and Xie Y: VDAC1 oligomerization may enhance DDP-induced hepatocyte apoptosis by exacerbating oxidative stress and mitochondrial DNA damage. FEBS Open Bio. 12:516–522. 2022. View Article : Google Scholar : PubMed/NCBI

Arbel N, Ben-Hail D and Shoshan-Barmatz V: Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J Biol Chem. 287:23152–23161. 2012. View Article : Google Scholar : PubMed/NCBI

Rosencrans WM, Rajendran M, Bezrukov SM and Rostovtseva TK: VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease. Cell Calcium. 94:1023562021. View Article : Google Scholar : PubMed/NCBI

Lu W and Kang Y: Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 49:361–374. 2019. View Article : Google Scholar

Qiu Z, Wang X, Yang Z, Liao S, Dong W, Sun T, Wu H, Zhang Q, Pan Z, Lam SM, et al: GBA1-dependent membrane glucosylceramide reprogramming promotes liver cancer metastasis via activation of the Wnt/β-catenin signalling pathway. Cell Death Dis. 13:5082022. View Article : Google Scholar : PubMed/NCBI

Cristofanon S and Fulda S: Correction: ABT-737 promotes tBid mitochondrial accumulation to enhance TRAIL-induced apoptosis in glioblastoma cells. Cell Death Dis. 15:6792024. View Article : Google Scholar : PubMed/NCBI

Assenat E, Ben Abdelghani M, Gourgou S, Perrier H, Akouz FK, Desgrippes R, Galais MP, Janiszewski C, Mazard T, Rinaldi Y, et al: Impact of lean body mass-based oxaliplatin dose calculation on neurotoxicity in adjuvant treatment of stage III colon cancer: Results of the Phase II randomized LEANOX trial. J Clin Oncol. 43:2616–2627. 2025. View Article : Google Scholar

Deng J, Paulus A, Fang DD, Manna A, Wang G, Wang H, Zhu S, Chen J, Min P, Yin Y, et al: Lisaftoclax (APG-2575) Is a Novel BCL-2 inhibitor with robust antitumor activity in preclinical models of hematologic malignancy. Clin Cancer Res. 28:5455–5468. 2022. View Article : Google Scholar : PubMed/NCBI

Sakai K, Inoue M, Mikami S, Nishimura H, Kuwabara Y, Kojima A, Toda M, Ogawa-Kobayashi Y, Kikuchi S, Hirata Y, et al: Functional inhibition of heat shock protein 70 by VER-155008 suppresses pleural mesothelioma cell proliferation via an autophagy mechanism. Thorac Cancer. 12:491–503. 2021. View Article : Google Scholar : PubMed/NCBI

Alsaab HO and Almalki AH: Anti-HSP70 alleviates cell migration and proliferation in colorectal cancer cells (CRC) by targeting CXCR4 (in vitro study). Med Oncol. 40:2562023. View Article : Google Scholar

Xu F, Lin D, Jiang W, Meng L, Xu Y, Wang C, Wang X, He H, Xu D and Zhu Y: HSP70 inhibitor VER155008 suppresses pheochromocytoma cell and xenograft growth by inhibition of PI3K/AKT/mTOR and MEK/ERK pathways. Int J Clin Exp Pathol. 12:2585–2594. 2019.

Lin X, Li L, Li S, Li Q, Xie D, Zhou M and Huang Y: Targeting the opening of mitochondrial permeability transition pores potentiates nanoparticle drug delivery and mitigates cancer metastasis. Adv Sci (Weinh). 8:20028342021. View Article : Google Scholar : PubMed/NCBI

Shuxian Y, Haiyan X and Li C: Recent advances in heat shock proteins in cancer diagnosis, prognosis, metabolism and treatment. Biomed Pharmacother. 142:1120742021. View Article : Google Scholar : PubMed/NCBI

Lai P, Liu L, Bancaro N, Troiani M, Calì B, Li Y, Chen J, Singh PK, Arzola RA, Attanasio G, et al: Mitochondrial DNA released by senescent tumor cells enhances PMN-MDSC-driven immunosuppression through the cGAS-STING pathway. Immunity. 58:811–825.e7. 2025. View Article : Google Scholar : PubMed/NCBI

Chen Y, Li Z, Chen X and Zhang S: Long non-coding RNAs: From disease code to drug role. Acta Pharm Sin B. 11:340–354. 2021. View Article : Google Scholar : PubMed/NCBI

Ertl HCJ: Immunogenicity and toxicity of AAV gene therapy. Front Immunol. 13:9758032022. View Article : Google Scholar

Chan YK, Wang SK, Chu CJ, Copland DA, Letizia AJ, Costa Verdera H, Chiang JJ, Sethi M, Wang MK, Neidermyer WJ Jr, et al: Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses. Sci Transl Med. 13:eabd34382021. View Article : Google Scholar : PubMed/NCBI

Knudson KM, Hicks KC, Luo X, Chen JQ, Schlom J and Gameiro SR: M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology. 7:e14265192018. View Article : Google Scholar : PubMed/NCBI

Zhang H, Zhang Y, Dong J, Zuo S, Meng G, Wu J and Wei J: Recombinant adenovirus expressing the fusion protein PD1PVR improves CD8(+) T cell-mediated antitumor efficacy with long-term tumor-specific immune surveillance in hepatocellular carcinoma. Cell Oncol (Dordr). 44:1243–1255. 2021. View Article : Google Scholar : PubMed/NCBI

Sun Y, Deng R and Zhang C: Erastin induces apoptotic and ferroptotic cell death by inducing ROS accumulation by causing mitochondrial dysfunction in gastric cancer cell HGC-27. Mol Med Rep. 22:2826–2832. 2020.PubMed/NCBI

Takeyama N, Miki S, Hirakawa A and Tanaka T: Role of the mitochondrial permeability transition and cytochrome C release in hydrogen peroxide-induced apoptosis. Exp Cell Res. 274:16–24. 2002. View Article : Google Scholar : PubMed/NCBI

Zhu W, Liang Q, Yang X, Yu Y, Shen X and Sun G: Combination of sorafenib and Valproic acid synergistically induces cell apoptosis and inhibits hepatocellular carcinoma growth via down-regulating Notch3 and pAkt. Am J Cancer Res. 7:2503–2514. 2017.PubMed/NCBI

Wang Q, Liu J, Chen Z, Zheng J, Wang Y and Dong J: Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed Pharmacother. 170:1160212024. View Article : Google Scholar : PubMed/NCBI

Liu Y, Song J, Shi Q, Chen B, Qiu W, Liu Y, Huang S and He X: Glucose-induced LINC01419 reprograms the glycolytic pathway by recruiting YBX1 to enhance PDK1 mRNA stability in hepatocellular carcinoma. Clin Transl Med. 14:e701222024. View Article : Google Scholar : PubMed/NCBI

Lv JL, Lai WQ, Gong YQ, Zheng KY, Zhang XY, Lu ZP, Li MW, Wang XY and Dai LS: Bombyx mori voltage-dependent anion-selective channel induces programmed cell death to defend against Bombyx mori nucleopolyhedrovirus infection. Pest Manag Sci. 80:3752–3762. 2024. View Article : Google Scholar

Ventura C, Junco M, Santiago Valtierra FX, Gooz M, Zhiwei Y, Townsend DM, Woster PM and Maldonado EN: Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival. Eur J Pharmacol. 957:1760342023. View Article : Google Scholar

Lan T, Gao F, Cai Y, Lv Y, Zhu J, Liu H, Xie S, Wan H, He H, Xie K, et al: The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment. Nat Commun. 16:3332025. View Article : Google Scholar : PubMed/NCBI

Wang Y, Zhu GQ, Yang R, Wang C, Qu WF, Chu TH, Tang Z, Yang C, Yang L, Zhou CW, et al: Deciphering intratumoral heterogeneity of hepatocellular carcinoma with microvascular invasion with radiogenomic analysis. J Transl Med. 21:7342023. View Article : Google Scholar : PubMed/NCBI

Wang Z, Cheng Y, Song Z and Zhao R: Pan-cancer analysis of voltage-dependent anion channel (VDAC1) as a cancer therapeutic target or diagnostic biomarker. Dis Markers. 2022:59461102022. View Article : Google Scholar : PubMed/NCBI

Fujita M, Chen MM, Siwak DR, Sasagawa S, Oosawa-Tatsuguchi A, Arihiro K, Ono A, Miura R, Maejima K, Aikata H, et al: Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets. Nat Commun. 13:64812022. View Article : Google Scholar : PubMed/NCBI

Brunelle JK and Letai A: Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 122((Pt 4)): 437–441. 2009. View Article : Google Scholar

Khan MW, Terry AR, Priyadarshini M, Ilievski V, Farooq Z, Guzman G, Cordoba-Chacon J, Ben-Sahra I, Wicksteed B and Layden BT: The hexokinase ‘HKDC1’ interaction with the mitochondria is essential for liver cancer progression. Cell Death Dis. 13:6602022. View Article : Google Scholar : PubMed/NCBI

Wang Z, Rehman AU, Qin X, Zhu C and Wu S: PI3K/AKT/mtor pathway-associated genes reveal a putative prognostic signature correlated with immune infiltration in hepatocellular carcinoma. Dis Markers. 2022:75456662022. View Article : Google Scholar : PubMed/NCBI

Wang Q, Shao X, Zhang Y, Zhu M, Wang FXC, Mu J, Li J, Yao H and Chen K: Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Med. 12:11149–11165. 2023. View Article : Google Scholar : PubMed/NCBI

Liu R, Guo Y, Wang L, Yin G, Tuo H, Zhu Y, Yang W, Liu Q and Wang Y: A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment. Cell Death Differ. 32:714–729. 2025. View Article : Google Scholar : PubMed/NCBI

Ramos LCB, Rodrigues FP, Biazzotto JC, de Paula Machado S, Slep LD, Hamblin MR and da Silva RS: Targeting the mitochondrial VDAC in hepatocellular carcinoma using a polyclonal antibody-conjugated to a nitrosyl ruthenium complex. J Biol Inorg Chem. 23:903–916. 2018. View Article : Google Scholar : PubMed/NCBI

Yang Y, Luo M, Zhang K, Zhang J, Gao T, Connell DO, Yao F, Mu C, Cai B, Shang Y and Chen W: Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun. 11:4332020. View Article : Google Scholar : PubMed/NCBI

Seliger B: Combinatorial approaches with checkpoint inhibitors to enhance anti-tumor immunity. Front Immunol. 10:9992019. View Article : Google Scholar

Zheng Y, Ye S, Huang S, Cheng Y, Zhang Y, Leng Y, He M, Wu E, Chen J, Kong L and Zhang H: Lefamulin overcomes acquired drug resistance via regulating mitochondrial homeostasis by targeting ILF3 in hepatocellular carcinoma. Adv Sci (Weinh). 11:e24017892024. View Article : Google Scholar : PubMed/NCBI

Hu Y, Zhou M, Tang J, Li S, Liu H, Hu J, Ma H, Liu J, Qin T, Yu X, et al: Efficacy and safety of stereotactic body radiotherapy combined with camrelizumab and apatinib in patients with hepatocellular carcinoma with portal vein tumor thrombus. Clin Cancer Res. 29:4088–4097. 2023. View Article : Google Scholar : PubMed/NCBI

Wang T, He M, Zhang X, Guo Z, Wang P and Long F: Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: A novel perspective. Cell Mol Biol Lett. 29:602024. View Article : Google Scholar

Seydi H, Nouri K, Rezaei N, Tamimi A, Hassan M, Mirzaei H and Vosough M: Autophagy orchestrates resistance in hepatocellular carcinoma cells. Biomed Pharmacother. 161:1144872023. View Article : Google Scholar : PubMed/NCBI

Song JQ, Shen LJ, Wang HJ, Liu QB, Ye LB, Liu K, Shi L, Cai B, Lin HS and Pang T: Discovery of balasubramide derivative with tissue-specific anti-inflammatory activity against acute lung injury by targeting VDAC1. Adv Sci (Weinh). 11:e24105502024. View Article : Google Scholar : PubMed/NCBI

Keiser MS, Ranum PT, Yrigollen CM, Carrell EM, Smith GR, Muehlmatt AL, Chen YH, Stein JM, Wolf RL, Radaelli E, et al: Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain. Nat Med. 27:1982–1989. 2021. View Article : Google Scholar : PubMed/NCBI

Kaushal A: Innate immune regulations and various siRNA modalities. Drug Deliv Transl Res. 13:2704–2718. 2023. View Article : Google Scholar : PubMed/NCBI

Zhang Z, Zhai M, Bao S, Sun X, Chen R, Wang B, Yang F, Yang L and Zhou M: Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas. J Adv Res. Jun 11–2025.(Epub ahead of print).

Li Y, Li XM, Wei LS and Ye JF: Advancements in mitochondrial-targeted nanotherapeutics: Overcoming biological obstacles and optimizing drug delivery. Front Immunol. 15:14519892024. View Article : Google Scholar

Xiao Y, He Z, Li W, Chen D, Niu X, Yang X, Zeng W, Wang M, Qian Y, Su Y, et al: A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy. Nat Commun. 16:13882025. View Article : Google Scholar : PubMed/NCBI

Monty MA, Islam MA, Nan X, Tan J, Tuhin IJ, Tang X, Miao M, Wu D and Yu L: Emerging role of RNA interference in immune cells engineering and its therapeutic synergism in immunotherapy. Br J Pharmacol. 178:1741–1755. 2021. View Article : Google Scholar

Kim J, Gupta R, Blanco LP, Yang S, Shteinfer-Kuzmine A, Wang K, Zhu J, Yoon HE, Wang X, Kerkhofs M, et al: VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science. 366:1531–1536. 2019. View Article : Google Scholar : PubMed/NCBI

Yang L, Zhu B, Zhou S, Zhao M, Li R, Zhou Y, Shi X, Han J, Zhang W and Zhou B: Mitochondrial dysfunction was involved in decabromodiphenyl ethane-induced glucolipid metabolism disorders and neurotoxicity in zebrafish larvae. Environ Sci Technol. 57:11043–11055. 2023. View Article : Google Scholar

Hu Y, Tian C, Chen F, Zhang A and Wang W: The mystery of methylmercury-perturbed calcium homeostasis: AMPK-DRP1-dependent mitochondrial fission initiates ER-mitochondria contact formation. Sci Total Environ. 923:1713982024. View Article : Google Scholar : PubMed/NCBI

Harter MF, Recaldin T, Gerard R, Avignon B, Bollen Y, Esposito C, Guja-Jarosz K, Kromer K, Filip A, Aubert J, et al: Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids. Nat Biomed Eng. 8:345–360. 2024. View Article : Google Scholar : PubMed/NCBI

Hu X, Zhang M, Quan C, Ren S, Chen W and Wang J: ROS-responsive and triple-synergistic mitochondria-targeted polymer micelles for efficient induction of ICD in tumor therapeutics. Bioact Mater. 36:490–507. 2024. View Article : Google Scholar : PubMed/NCBI