Convergence of epithelial-mesenchymal transition and mitochondrial dynamics: Mechanisms and therapeutic opportunities in cancer metastasis

Abstract

Epithelial-mesenchymal transition (EMT) is a biological process in which epithelial cells acquire mesenchymal characteristics, including enhanced motility. While EMT plays essential roles in embryonic development and tissue repair, its dysregulation is closely associated with cancer metastasis and fibrotic diseases. The active and context-dependent energy demands of EMT highlight the importance of mitochondrial function and dynamics, particularly mitochondrial fusion and fission, in facilitating EMT. Recent findings reveal a critical yet underexplored role of mitochondrial dynamics, especially fusion and fission, in supporting EMT and cancer metastasis through metabolic reprogramming and redox signaling. Dysregulation of mitochondrial dynamics has been implicated in EMT-related diseases, especially cancer and fibrosis, both of which share common pathological features such as chronic inflammation, extracellular matrix remodeling, and sustained EMT activation. Despite growing interest, the intersection of mitochondrial dynamics, stress responses, and EMT remains insufficiently studied, particularly in the context of progressive diseases such as cancer. This review addresses this gap by exploring the interplay between mitochondrial dynamics and EMT in cancer metastasis, highlighting potential vulnerabilities and therapeutic opportunities. Understanding the convergence of EMT and mitochondrial dynamics offers a novel perspective on cancer progression and paves the way for targeted interventions. Moreover, the study of mitochondrial dynamics in fibrosis may provide insights for therapeutic strategies against cancer metastasis.

Keywords

Mitochondrial dynamics / Mitochondrial fusion / Mitochondrial fission / Epithelial-mesenchymal transition / Cancer / Fibrosis

References

[1] López-Novoa JM, Nieto MA. Inflammation and EMT: An alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009; 1(6-7):303-314. doi: 10.1002/emmm.200900043

[2] Hay ED.An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995; 154(1):8-20. doi: 10.1159/000147748

[3] Akhurst RJ. From shape-shifting embryonic cells to oncology: The fascinating history of epithelial mesenchymal transition. Semin Cancer Biol. 2023; 96:100-114. doi: 10.1016/j.semcancer.2023.10.003

[4] Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016; 166(1):21-45. doi: 10.1016/j.cell.2016.06.028

[5] Kalluri R, Weinberg RA. The basics of epithelial- mesenchymal transition [published correction appears in J Clin Invest. 2010 May 3;120(5):1786]. J Clin Invest. 2009; 119(6):1420-1428. doi: 10.1172/JCI39104

[6] Chen T, You Y, Jiang H, Wang ZZ. Epithelial-mesenchymal transition (EMT): A biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol. 2017; 232(12):3261-3272. doi: 10.1002/jcp.25797

[7] Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 2011;27:347-376. doi: 10.1146/annurev-cellbio-092910-154036

[8] Lamouille S, Xu J, Derynck R.Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3):178-196. doi: 10.1038/nrm3758

[9] Zhang J, Tian XJ, Xing J. Signal transduction pathways of EMT induced by TGF-β SHH, and WNT and their crosstalks. J Clin Med. 2016; 5(4):41. doi: 10.3390/jcm5040041

[10] Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7(344):re8. doi: 10.1126/scisignal.2005189

[11] Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial- mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-890. doi: 10.1016/j.cell.2009.11.007

[12] Johar K, Vasavada AR, Tatsumi K, Dholakia S, Nihalani B, Rao SS. Anterior capsular plaque in congenital cataract: Occurrence, morphology, immunofluorescence, and ultrastructure. Invest Ophthalmol Vis Sci. 2007; 48(9):4209-4214. doi: 10.1167/iovs.07-0312

[13] Pastushenko I, Blanpain C. EMT Transition states during tumor progression and metastasis. Trends Cell Biol. 2019; 29(3):212-226. doi: 10.1016/j.tcb.2018.12.001

[14] Smith BN, Bhowmick NA. Role of EMT in metastasis and therapy resistance. J Clin Med. 2016; 5(2):17. doi: 10.3390/jcm5020017

[15] Sabouni E, Nejad MM, Mojtabavi S, et al. Unraveling the function of epithelial-mesenchymal transition (EMT) in colorectal cancer: Metastasis, therapy response, and revisiting molecular pathways. Biomed Pharmacother. 2023;160:114395. doi: 10.1016/j.biopha.2023.114395

[16] Bhatia S, Wang P, Toh A, Thompson EW. New insights into the role of phenotypic plasticity and EMT in driving cancer progression. Front Mol Biosci. 2020;7:71. doi: 10.3389/fmolb.2020.00071

[17] Taki M, Abiko K, Ukita M, et al. Tumor immune microenvironment during epithelial-mesenchymal transition. Clin Cancer Res. 2021; 27(17):4669-4679. doi: 10.1158/1078-0432.CCR-20-4459

[18] Dudas J, Ladanyi A, Ingruber J, Steinbichler TB, Riechelmann H. Epithelial to mesenchymal transition: A mechanism that fuels cancer radio/chemoresistance. Cells. 2020; 9(2):428. doi: 10.3390/cells9020428

[19] Yu SB, Pekkurnaz G. Mechanisms orchestrating mitochondrial dynamics for energy homeostasis. J Mol Biol. 2018; 430(21):3922-3941. doi: 10.1016/j.jmb.2018.07.027

[20] Liesa M, Shirihai OS. Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab. 2013; 17(4):491-506. doi: 10.1016/j.cmet.2013.03.002

[21] Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927; 8(6):519-530. doi: 10.1085/jgp.8.6.519

[22] Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011; 194(1):7-15. doi: 10.1083/jcb.201102095

[23] Shiratori R, Furuichi K, Yamaguchi M, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019; 9(1):18699. doi: 10.1038/s41598-019-55296-3

[24] Jia D, Park JH, Jung KH, Levine H, Kaipparettu BA. Elucidating the metabolic plasticity of cancer: Mitochondrial reprogramming and hybrid metabolic states. Cells. 2018; 7(3):21. doi: 10.3390/cells7030021

[25] Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009; 417(1):1-13. doi: 10.1042/BJ20081386

[26] Su X, Yang Y, Guo C, et al. NOX4-derived ROS mediates TGF-β1-induced metabolic reprogramming during epithelial-mesenchymal transition through the PI3K/AKT/ HIF-1α pathway in glioblastoma. Oxid Med Cell Longev. 2021;2021:5549047. doi: 10.1155/2021/5549047

[27] Zhou G, Dada LA, Wu M, et al.Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol. 2009; 297(6):L1120-L1130. doi: 10.1152/ajplung.00007.2009

[28] Gordan JD, Simon MC. Hypoxia-inducible factors: Central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007; 17(1):71-77. doi: 10.1016/j.gde.2006.12.006

[29] Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018; 20(7):745-754. doi: 10.1038/s41556-018-0124-1

[30] Javadov S, Kozlov AV, Camara AKS.Mitochondria in health and diseases. Cells. 2020; 9(5):1177. doi: 10.3390/cells9051177

[31] Annesley SJ, Fisher PR.Mitochondria in health and disease. Cells. 2019; 8(7):680. doi: 10.3390/cells8070680

[32] Cloonan SM, Choi AM.Mitochondria in lung disease. J Clin Invest. 2016; 126(3):809-820. doi: 10.1172/JCI81113

[33] Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun. 2017; 482(3):426-431. doi: 10.1016/j.bbrc.2016.11.088

[34] Abate M, Festa A, Falco M, et al. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol. 2020; 98:139-153. doi: 10.1016/j.semcdb.2019.05.022

[35] Greiner S, Sobanski J, Bock R. Why are most organelle genomes transmitted maternally? Bioessays. 2015; 37(1):80-94. doi: 10.1002/bies.201400110

[36] Birky CW Jr. Uniparental inheritance of mitochondrial and chloroplast genes: Mechanisms and evolution. Proc Natl Acad Sci U S A. 1995; 92(25):11331-11338. doi: 10.1073/pnas.92.25.11331

[37] Cummins JM. The role of maternal mitochondria during oogenesis, fertilization and embryogenesis. Reprod Biomed Online. 2002; 4(2):176-182. doi: 10.1016/s1472-6483(10)61937-2

[38] Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity. 2015; 42(3):406-417. doi: 10.1016/j.immuni.2015.02.002

[39] Tait SW, Green DR.Mitochondria and cell signalling. J Cell Sci. 2012; 125(Pt 4):807-815. doi: 10.1242/jcs.099234

[40] Kuznetsov AV, Margreiter R, Ausserlechner MJ, Hagenbuchner J.The complex interplay between mitochondria, ROS and entire cellular metabolism. Antioxidants (Basel). 2022; 11(10):1995. doi: 10.3390/antiox11101995

[41] Chan DC. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol. 2006; 22:79-99. doi: 10.1146/annurev.cellbio.22.010305.104638

[42] Chen H, Chan DC.Physiological functions of mitochondrial fusion. Ann N Y Acad Sci. 2010; 1201:21-25. doi: 10.1111/j.1749-6632.2010.05615.x

[43] van der Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol. 2013; 5(6):a011072. doi: 10.1101/cshperspect.a011072

[44] Wai T, Langer T.Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016; 27(2):105-117. doi: 10.1016/j.tem.2015.12.001

[45] Dai W, Jiang L. Dysregulated mitochondrial dynamics and metabolism in obesity, diabetes and cancer. Front Endocrinol (Lausanne). 2019;10:570. doi: 10.3389/fendo.2019.00570

[46] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3):209-249. doi: 10.3322/caac.21660

[47] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024 [published correction appears in CA Cancer J Clin. 2024 Mar-Apr;74(2):203. doi: 10.3322/caac.21830.]. CA Cancer J Clin. 2024; 74(1):12-49. doi: 10.3322/caac.21820

[48] Maher TM, Bendstrup E, Dron L, et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res. 2021; 22(1):197. doi: 10.1186/s12931-021-01791-z

[49] Chen H, Chan DC. Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab. 2017; 26(1):39-48. doi: 10.1016/j.cmet.2017.05.016

[50] Simula L, Nazio F, Campello S. The mitochondrial dynamics in cancer and immune-surveillance. Semin Cancer Biol. 2017; 47:29-42. doi: 10.1016/j.semcancer.2017.06.007

[51] Gibb AA, Lazaropoulos MP, Elrod JW. Myofibroblasts and fibrosis: Mitochondrial and metabolic control of cellular differentiation. Circ Res. 2020; 127(3):427-447. doi: 10.1161/CIRCRESAHA.120.316958

[52] Li X, Zhang W, Cao Q, et al. Mitochondrial dysfunction in fibrotic diseases. Cell Death Discov. 2020;6:80. doi: 10.1038/s41420-020-00316-9

[53] Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: Mechanisms and potential targets. Signal Transduct Target Ther. 2023; 8(1):333. doi: 10.1038/s41392-023-01547-9

[54] Liu BH, Xu CZ, Liu Y, et al. Mitochondrial quality control in human health and disease. Mil Med Res. 2024; 11(1):32. doi: 10.1186/s40779-024-00536-5

[55] Sessions DT, Kashatus DF. Mitochondrial dynamics in cancer stem cells. Cell Mol Life Sci. 2021; 78(8):3803-3816. doi: 10.1007/s00018-021-03773-2

[56] Wu Z, Xiao C, Li F, Huang W, You F, Li X. Mitochondrial fusion-fission dynamics and its involvement in colorectal cancer. Mol Oncol. 2024; 18(5):1058-1075. doi: 10.1002/1878-0261.13578

[57] Srinivasan S, Guha M, Kashina A, Avadhani NG. Mitochondrial dysfunction and mitochondrial dynamics- The cancer connection. Biochim Biophys Acta Bioenerg. 2017; 1858(8):602-614. doi: 10.1016/j.bbabio.2017.01.004

[58] Rodrigues T, Ferraz LS. Therapeutic potential of targeting mitochondrial dynamics in cancer. Biochem Pharmacol. 2020;182:114282. doi: 10.1016/j.bcp.2020.114282

[59] Tábara LC, Segawa M, Prudent J.Molecular mechanisms of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2025; 26(2):123-146. doi: 10.1038/s41580-024-00785-1

[60] Madan S, Uttekar B, Chowdhary S, Rikhy R. Mitochondria lead the way: Mitochondrial dynamics and function in cellular movements in development and disease. Front Cell Dev Biol. 2022;9:781933. doi: 10.3389/fcell.2021.781933

[61] Adebayo M, Singh S, Singh AP, Dasgupta S. Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis. FASEB J. 2021; 35(6):e21620. doi: 10.1096/fj.202100067R

[62] Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: Overview of molecular mechanisms. Essays Biochem. 2018; 62(3):341-360. doi: 10.1042/EBC20170104

[63] Altieri DC.Mitochondrial dynamics and metastasis. Cell Mol Life Sci. 2019; 76(5):827-835. doi: 10.1007/s00018-018-2961-2

[64] Ma Y, Wang L, Jia R. The role of mitochondrial dynamics in human cancers. Am J Cancer Res. 2020; 10(5):1278-1293.

[65] Grandemange S, Herzig S, Martinou JC.Mitochondrial dynamics and cancer. Semin Cancer Biol. 2009; 19(1):50-56. doi: 10.1016/j.semcancer.2008.12.001

[66] Wang Y, Liu HH, Cao YT, Zhang LL, Huang F, Yi C. The role of mitochondrial dynamics and mitophagy in carcinogenesis, metastasis and therapy. Front Cell Dev Biol. 2020;8:413. doi: 10.3389/fcell.2020.00413

[67] Maycotte P, Marín-Hernández A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortés-Hernández P.Mitochondrial dynamics and cancer. Tumour Biol. 2017; 39(5):1010428317698391. doi: 10.1177/1010428317698391

[68] Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: A strained relationship. Biochim Biophys Acta Rev Cancer. 2020; 1873(2): 188356. doi: 10.1016/j.bbcan.2020.188356

[69] Landolt L, Spagnoli GC, Hertig A, Brocheriou I, Marti HP. Fibrosis and cancer: Shared features and mechanisms suggest common targeted therapeutic approaches. Nephrol Dial Transplant. 2022; 37(6):1024-1032. doi: 10.1093/ndt/gfaa301

[70] Hu C, Zhao Y, Wang X, Zhu T. Intratumoral fibrosis in facilitating renal cancer aggressiveness: Underlying mechanisms and promising targets. Front Cell Dev Biol. 2021;9:651620. doi: 10.3389/fcell.2021.651620

[71] Abu Qubo A, Numan J, Snijder J, et al. Idiopathic pulmonary fibrosis and lung cancer: Future directions and challenges. Breathe (Sheff). 2022; 18(4):220147. doi: 10.1183/20734735.0147-2022

[72] Dhar D, Baglieri J, Kisseleva T, Brenner DA. Mechanisms of liver fibrosis and its role in liver cancer. Exp Biol Med (Maywood). 2020; 245(2):96-108. doi: 10.1177/1535370219898141

[73] Mishra P, Chan DC. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol. 2014; 15(10):634-646. doi: 10.1038/nrm3877

[74] Colpman P, Dasgupta A, Archer SL. The role of mitochondrial dynamics and mitotic fission in regulating the cell cycle in cancer and pulmonary arterial hypertension: Implications for dynamin-related protein 1 and mitofusin2 in hyperproliferative diseases. Cells. 2023; 12(14):1897. doi: 10.3390/cells12141897

[75] Youle RJ, Narendra DP.Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011; 12(1):9-14. doi: 10.1038/nrm3028

[76] Suen DF, Norris KL, Youle RJ.Mitochondrial dynamics and apoptosis. Genes Dev. 2008; 22(12):1577-1590. doi: 10.1101/gad.1658508

[77] Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010; 11(12):872-884. doi: 10.1038/nrm3013

[78] Al Ojaimi M, Salah A, El-Hattab AW. Mitochondrial fission and fusion: molecular mechanisms, biological functions, and related disorders. Membranes (Basel). 2022; 12(9):893. doi: 10.3390/membranes12090893

[79] Bertholet AM, Delerue T, Millet AM, et al. Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis. 2016; 90:3-19. doi: 10.1016/j.nbd.2015.10.011

[80] Marín-García J, Akhmedov AT. Mitochondrial dynamics and cell death in heart failure. Heart Fail Rev. 2016; 21(2):123-136. doi: 10.1007/s10741-016-9530-2

[81] Kraus F, Ryan MT. The constriction and scission machineries involved in mitochondrial fission. J Cell Sci. 2017; 130(18):2953-2960. doi: 10.1242/jcs.199562

[82] Bui HT, Shaw JM. Dynamin assembly strategies and adaptor proteins in mitochondrial fission. Curr Biol. 2013; 23(19):R891-R899. doi: 10.1016/j.cub.2013.08.040

[83] Losón OC, Song Z, Chen H, Chan DC. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell. 2013; 24(5):659-667. doi: 10.1091/mbc.E12-10-0721

[84] Liu R, Chan DC.The mitochondrial fission receptor Mff selectively recruits oligomerized Drp1. Mol Biol Cell. 2015; 26(24):4466-4477. doi: 10.1091/mbc.E15-08-0591

[85] Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell. 2001; 12(8):2245-2256. doi: 10.1091/mbc.12.8.2245

[86] Ingerman E, Perkins EM, Marino M, et al. Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol. 2005; 170(7):1021-1027. doi: 10.1083/jcb.200506078

[87] Fransson S, Ruusala A, Aspenström P. The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun. 2006; 344(2):500-510. doi: 10.1016/j.bbrc.2006.03.163

[88] Mears JA, Lackner LL, Fang S, Ingerman E, Nunnari J, Hinshaw JE. Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat Struct Mol Biol. 2011; 18(1):20-26. doi: 10.1038/nsmb.1949

[89] Ji WK, Hatch AL, Merrill RA, Strack S, Higgs HN. Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. Elife. 2015;4:e11553. doi: 10.7554/eLife.11553

[90] Hatch AL, Gurel PS, Higgs HN. Novel roles for actin in mitochondrial fission. J Cell Sci. 2014; 127(Pt 21):4549-4560. doi: 10.1242/jcs.153791

[91] Korobova F, Ramabhadran V, Higgs HN.An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science. 2013; 339(6118):464-467. doi: 10.1126/science.1228360

[92] Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. ER tubules mark sites of mitochondrial division. Science. 2011; 334(6054):358-362. doi: 10.1126/science.1207385

[93] Wang YH, Wang JQ, Wang Q, et al. Endophilin B2 promotes inner mitochondrial membrane degradation by forming heterodimers with Endophilin B1 during mitophagy. Sci Rep. 2016;6:25153. doi: 10.1038/srep25153

[94] Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007; 282(15):11521-11529. doi: 10.1074/jbc.M607279200

[95] Xie B, Wang S, Jiang N, Li JJ. Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance. Cancer Lett. 2019; 443:56-66. doi: 10.1016/j.canlet.2018.11.019

[96] Rong R, Xia X, Peng H, et al. Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy. Cell Death Dis. 2020; 11(9):720. doi: 10.1038/s41419-020-02922-y

[97] Cho B, Cho HM, Kim HJ, et al. CDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation. Exp Mol Med. 2014; 46(7):e105. doi: 10.1038/emm.2014.36

[98] Cribbs JT, Strack S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 2007; 8(10):939-944. doi: 10.1038/sj.embor.7401062

[99] Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007; 282(30):21583-21587. doi: 10.1074/jbc.C700083200

[100] Kashatus JA, Nascimento A, Myers LJ, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell. 2015; 57(3):537-551. doi: 10.1016/j.molcel.2015.01.002

[101] Wang W, Wang Y, Long J, et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 2012; 15(2):186-200. doi: 10.1016/j.cmet.2012.01.009

[102] Yan J, Liu XH, Han MZ, et al. Blockage of GSK3β-mediated Drp1 phosphorylation provides neuroprotection in neuronal and mouse models of Alzheimer’s disease. Neurobiol Aging. 2015; 36(1):211-227. doi: 10.1016/j.neurobiolaging.2014.08.005

[103] Nakamura N, Kimura Y, Tokuda M, Honda S, Hirose S. MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology. EMBO Rep. 2006; 7(10):1019-1022. doi: 10.1038/sj.embor.7400790

[104] Karbowski M, Neutzner A, Youle RJ. The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol. 2007; 178(1):71-84. doi: 10.1083/jcb.200611064

[105] Wang H, Song P, Du L, et al. Parkin ubiquitinates Drp1 for proteasome-dependent degradation: Implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem. 2011; 286(13):11649-11658. doi: 10.1074/jbc.M110.144238

[106] Harder Z, Zunino R, McBride H. Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol. 2004; 14(4):340-345. doi: 10.1016/j.cub.2004.02.004

[107] Zunino R, Schauss A, Rippstein P, Andrade-Navarro M, McBride HM. The SUMO protease SENP5 is required to maintain mitochondrial morphology and function. J Cell Sci. 2007; 120(Pt 7):1178-1188. doi: 10.1242/jcs.03418

[108] Guo C, Hildick KL, Luo J, Dearden L, Wilkinson KA, Henley JM. SENP3-mediated deSUMOylation of dynamin- related protein 1 promotes cell death following ischaemia. EMBO J. 2013; 32(11):1514-1528. doi: 10.1038/emboj.2013.65

[109] Wasiak S, Zunino R, McBride HM. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol. 2007; 177(3):439-450. doi: 10.1083/jcb.200610042

[110] Boulton DP, Caino MC. Mitochondrial fission and fusion in tumor progression to metastasis. Front Cell Dev Biol. 2022;10:849962. doi: 10.3389/fcell.2022.849962

[111] Nagdas S, Kashatus JA, Nascimento A, et al. Drp1 promotes KRas-driven metabolic changes to drive pancreatic tumor growth. Cell Rep. 2019; 28(7):1845- 1859.e5. doi: 10.1016/j.celrep.2019.07.031

[112] Wang Y, Patti GJ. The Warburg effect: A signature of mitochondrial overload. Trends Cell Biol. 2023; 33(12):1014-1020. doi: 10.1016/j.tcb.2023.03.013

[113] Gao T, Zhang X, Zhao J, et al. SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer. Cancer Lett. 2020; 469:89-101. doi: 10.1016/j.canlet.2019.10.029

[114] Inoue-Yamauchi A, Oda H. Depletion of mitochondrial fission factor DRP1 causes increased apoptosis in human colon cancer cells. Biochem Biophys Res Commun. 2012; 421(1):81-85. doi: 10.1016/j.bbrc.2012.03.118

[115] Liberti MV, Locasale JW. The Warburg effect: How does it benefit cancer cells? [published correction appears in Trends Biochem Sci. 2016 Mar;41(3):287] [published correction appears in Trends Biochem Sci. 2016 Mar;41(3):287. doi: 10.1016/j.tibs.2016.01.004.]. Trends Biochem Sci. 2016; 41(3):211-218. doi: 10.1016/j.tibs.2015.12.001

[116] Warburg O. On the origin of cancer cells. Science. 1956; 123(3191):309-314. doi: 10.1126/science.123.3191.309

[117] Paul S, Ghosh S, Kumar S. Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol. 2022; 86(Pt 3):1216-1230. doi: 10.1016/j.semcancer.2022.09.007

[118] Zhou D, Duan Z, Li Z, Ge F, Wei R, Kong L. The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment. Front Pharmacol. 2022;13:1091779. doi: 10.3389/fphar.2022.1091779

[119] Beckner ME, Stracke ML, Liotta LA, Schiffmann E. Glycolysis as primary energy source in tumor cell chemotaxis. J Natl Cancer Inst. 1990; 82(23):1836-1840. doi: 10.1093/jnci/82.23.1836

[120] Benej M, Papandreou I, Denko NC. Hypoxic adaptation of mitochondria and its impact on tumor cell function. Semin Cancer Biol. 2024; 100:28-38. doi: 10.1016/j.semcancer.2024.03.004

[121] Schito L, Semenza GL. Hypoxia-inducible factors: Master regulators of cancer progression. Trends Cancer. 2016; 2(12):758-770. doi: 10.1016/j.trecan.2016.10.016

[122] Chouaib S, Messai Y, Couve S, Escudier B, Hasmim M, Noman MZ. Hypoxia promotes tumor growth in linking angiogenesis to immune escape. Front Immunol. 2012;3:21. doi: 10.3389/fimmu.2012.00021

[123] Liao D, Johnson RS. Hypoxia: A key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 2007; 26(2):281-290. doi: 10.1007/s10555-007-9066-y

[124] Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016; 39:43-52. doi: 10.1016/j.ceb.2016.02.001

[125] Bao D, Zhao J, Zhou X, et al. Mitochondrial fission- induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene. 2019; 38(25):5007-5020. doi: 10.1038/s41388-019-0772-z

[126] Huang Q, Zhan L, Cao H, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016; 12(6):999-1014. doi: 10.1080/15548627.2016.1166318

[127] Zhan L, Cao H, Wang G, et al. Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma. Oncotarget. 2016; 7(40):65001-65011. doi: 10.18632/oncotarget.11339

[128] Han L, Zhang C, Wang D, et al.Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1. Oncogene. 2023; 42(13):1024-1037. doi: 10.1038/s41388-023-02621-w

[129] Yi T, Luo H, Qin F, et al. LncRNA LL22NC03-N14H11.1 promoted hepatocellular carcinoma progression through activating MAPK pathway to induce mitochondrial fission. Cell Death Dis. 2020; 11(10):832. doi: 10.1038/s41419-020-2584-z

[130] Merkel AL, Meggers E, Ocker M. PIM1 kinase as a target for cancer therapy. Expert Opin Investig Drugs. 2012; 21(4):425-436. doi: 10.1517/13543784.2012.668527

[131] Brault L, Gasser C, Bracher F, Huber K, Knapp S, Schwaller J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010; 95(6):1004-1015. doi: 10.3324/haematol.2009.017079

[132] Chua HH, Chang MH, Chen YH, et al. PIM1-induced cytoplasmic expression of RBMY mediates hepatocellular carcinoma metastasis. Cell Mol Gastroenterol Hepatol. 2023; 15(1):121-152. doi: 10.1016/j.jcmgh.2022.09.014

[133] Sun Z, Jiang Q, Li J, Guo J. The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis. Signal Transduct Target Ther. 2020; 5(1):150. doi: 10.1038/s41392-020-00265-w

[134] Dittmer J. The role of the transcription factor Ets1 in carcinoma. Semin Cancer Biol. 2015; 35:20-38. doi: 10.1016/j.semcancer.2015.09.010

[135] Ghosh D, Pakhira S, Ghosh DD, Roychoudhury S, Roy SS. Ets1 facilitates EMT/invasion through Drp1-mediated mitochondrial fragmentation in ovarian cancer. iScience. 2023; 26(9):107537. doi: 10.1016/j.isci.2023.107537

[136] Kugel S, Sebastián C, Fitamant J, et al. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell. 2016; 165(6):1401-1415. doi: 10.1016/j.cell.2016.04.033

[137] Bandopadhyay S, Prasad P, Ray U, Das Ghosh D, Roy SS. SIRT6 promotes mitochondrial fission and subsequent cellular invasion in ovarian cancer. FEBS Open Bio. 2022; 12(9):1657-1676. doi: 10.1002/2211-5463.13452

[138] Zhao J, Zhang J, Yu M, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013; 32(40):4814-4824. doi: 10.1038/onc.2012.494

[139] Xing J, Qi L, Liu X, Shi G, Sun X, Yang Y. Rolesofmitochondrial fusion and fission in breast cancer progression: A systematic review. World J Surg Oncol. 2022; 20(1):331. doi: 10.1186/s12957-022-02799-5

[140] Humphries BA, Cutter AC, Buschhaus JM, et al. Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer. Breast Cancer Res. 2020; 22(1):60. doi: 10.1186/s13058-020-01301-x

[141] Kuang J, Liu H, Feng L, Xue Y, Tang H, Xu P. How mitochondrial dynamics imbalance affects the progression of breast cancer: A mini review. Med Oncol. 2024; 41(10):238. doi: 10.1007/s12032-024-02479-2

[142] Pang X, Li TJ, Shi RJ, et al. IRF2BP2 drives lymphatic metastasis in OSCC cells by elevating mitochondrial fission-dependent fatty acid oxidation. Mol Carcinog. 2024; 63(1):45-60. doi: 10.1002/mc.23635

[143] Wang Z, Tang S, Cai L, et al. DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma. Br J Cancer. 2024; 130(11):1744-1757. doi: 10.1038/s41416-024-02670-2

[144] Neel DS, Allegakoen DV, Olivas V, et al. Differential subcellular localization regulates oncogenic signaling by ROS1 kinase fusion proteins. Cancer Res. 2019; 79(3):546-556. doi: 10.1158/0008-5472.CAN-18-1492

[145] Chang YJ, Chen KW, Chen L. Mitochondrial ROS 1 increases mitochondrial fission and respiration in oral squamous cancer carcinoma. Cancers (Basel). 2020; 12(10):2845. doi: 10.3390/cancers12102845

[146] Lei X, Lin H, Wang J, et al. Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression. Nat Commun. 2022; 13(1):3882. doi: 10.1038/s41467-022-31417-x

[147] Wu K, Mao YY, Chen Q, et al. Hypoxia-induced ROSpromotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma. Cell Oncol (Dordr). 2021; 44(5):1167-1181. doi: 10.1007/s13402-021-00629-6

[148] Ma C, Fan L, Wang J, Hao L, He J.Hippo/Mst1 overexpression induces mitochondrial death in head and neck squamous cell carcinoma via activating β-catenin/Drp1 pathway. Cell Stress Chaperones. 2019; 24(4):807-816. doi: 10.1007/s12192-019-01008-9

[149] Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015; 21(11):1253-1261. doi: 10.1038/nm.3981

[150] Sun Q, Hao Q, Prasanth KV. Nuclear long noncoding RNAs: Key regulators of gene expression. Trends Genet. 2018; 34(2):142-157. doi: 10.1016/j.tig.2017.11.005

[151] Tian T, Lv X, Pan G, et al. Long noncoding RNA MPRL promotes mitochondrial fission and cisplatin chemosensitivity via disruption of pre-miRNA processing. Clin Cancer Res. 2019; 25(12):3673-3688. doi: 10.1158/1078-0432.CCR-18-2739

[152] Fan S, Tian T, Lv X, et al. lncRNA CISAL inhibits BRCA1 transcription by forming a tertiary structure at its promoter. iScience. 2020; 23(2):100835. doi: 10.1016/j.isci.2020.100835

[153] Phan TTT, Lin YC, Chou YT, Wu CW, Lin LY. Tumor suppressor p53 restrains cancer cell dissemination by modulating mitochondrial dynamics. Oncogenesis. 2022; 11(1):26. doi: 10.1038/s41389-022-00401-x

[154] Guo J, Ye F, Jiang X, et al. Drp1 mediates high glucose- induced mitochondrial dysfunction and epithelial- mesenchymal transition in endometrial cancer cells. Exp Cell Res. 2020; 389(1):111880. doi: 10.1016/j.yexcr.2020.111880

[155] Zhang L, Sun L, Wang L, et al. Mitochondrial division inhibitor (mdivi-1) inhibits proliferation and epithelial- mesenchymal transition via the NF-κB pathway in thyroid cancer cells. Toxicol In Vitro. 2023;88:105552. doi: 10.1016/j.tiv.2023.105552

[156] Manczak M, Kandimalla R, Yin X, Reddy PH. Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity [published correction appears in Hum Mol Genet. 2019 Mar 1;28(5):875-876. doi: 10.1093/hmg/ddy399.]. Hum Mol Genet. 2019; 28(2):177-199. doi: 10.1093/hmg/ddy335

[157] Ferreira-da-Silva A, Valacca C, Rios E, et al. Mitochondrial dynamics protein Drp1 is overexpressed in oncocytic thyroid tumors and regulates cancer cell migration. PLoS One. 2015; 10(3):e0122308. doi: 10.1371/journal.pone.0122308

[158] Liu GY, Wang H, Ran R, Wang YC, Li Y. The GLI2/CDH6 axis enhances migration, invasion and mitochondrial fission of stomach adenocarcinoma cells. Biochem Biophys Res Commun. 2023; 676:182-189. doi: 10.1016/j.bbrc.2023.07.038

[159] Di Gregorio J, Robuffo I, Spalletta S, et al. The epithelial-to-mesenchymal transition as a possible therapeutic target in fibrotic disorders. Front Cell Dev Biol. 2020;8:607483. doi: 10.3389/fcell.2020.607483

[160] Herrera J, Henke CA, Bitterman PB. Extracellular matrix as a driver of progressive fibrosis. J Clin Invest. 2018; 128(1):45-53. doi: 10.1172/JCI93557

[161] Sun K, Li X, Scherer PE. Extracellular matrix (ECM) and fibrosis in adipose tissue: Overview and perspectives. Compr Physiol. 2023; 13(1):4387-4407. doi: 10.1002/cphy.c220020

[162] Chang EM, Chao CC, Wang MT, Hsu CL, Chen PC. PM2.5 promotes pulmonary fibrosis by mitochondrial dysfunction. Environ Toxicol. 2023; 38(8):1905-1913. doi: 10.1002/tox.23817

[163] Zhang J, Li WJ, Chen SQ, et al. Mutual promotion of mitochondrial fission and oxidative stress contributes to mitochondrial-DNA-mediated inflammation and epithelial- mesenchymal transition in paraquat-induced pulmonary fibrosis. World J Emerg Med. 2023; 14(3):209-216. doi: 10.5847/wjem.j.1920-8642.2023.057

[164] Mao C, Zhang J, Lin S, et al. MiRNA-30a inhibits AECs-II apoptosis by blocking mitochondrial fission dependent on Drp-1. J Cell Mol Med. 2014; 18(12):2404-2416. doi: 10.1111/jcmm.12420

[165] Zhang J, Xu P, Wang Y, et al. Astaxanthin prevents pulmonary fibrosis by promoting myofibroblast apoptosis dependent on Drp1-mediated mitochondrial fission. J Cell Mol Med. 2015; 19(9):2215-2231. doi: 10.1111/jcmm.12609

[166] Shi Y, Tao M, Ma X, et al. Delayed treatment with an autophagy inhibitor 3-MA alleviates the progression of hyperuricemic nephropathy. Cell Death Dis. 2020; 11(6):467. doi: 10.1038/s41419-020-2673-z

[167] Zhang J, Xie W, Ni B, et al. NSD 2 modulates Drp1- mediated mitochondrial fission in chronic renal allograft interstitial fibrosis by methylating STAT1. Pharmacol Res. 2024;200:107051. doi: 10.1016/j.phrs.2023.107051

[168] Kanlaya R, Subkod C, Nanthawuttiphan S, Thongboonkerd V. The protective effect of caffeine against oxalate-induced epithelial-mesenchymal transition in renal tubular cells via mitochondrial preservation. Biomed Pharmacother. 2024;171:116144. doi: 10.1016/j.biopha.2024.116144

[169] Ahmad AA, Draves SO, Rosca M.Mitochondria in diabetic kidney disease. Cells. 2021; 10(11):2945. doi: 10.3390/cells10112945

[170] Zhang HF, Liu HM, Xiang JY, et al. Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation. Acta Pharmacol Sin. 2023; 44(5):1051-1065. doi: 10.1038/s41401-022-00997-1

[171] Ayanga BA, Badal SS, Wang Y, et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J Am Soc Nephrol. 2016; 27(9):2733-2747. doi: 10.1681/ASN.2015101096

[172] Bhargava P, Schnellmann RG.Mitochondrial energetics in the kidney. Nat Rev Nephrol. 2017; 13(10):629-646. doi: 10.1038/nrneph.2017.107

[173] Guo K, Lu J, Huang Y, et al. Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PLoS One. 2015; 10(4):e0125176. doi: 10.1371/journal.pone.0125176

[174] Perry HM, Huang L, Wilson RJ, et al. Dynamin-related protein 1 deficiency promotes recovery from AKI. J Am Soc Nephrol. 2018; 29(1):194-206. doi: 10.1681/ASN.2017060659

[175] Puigserver P, Spiegelman BM. Peroxisome proliferator- activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): Transcriptional coactivator and metabolic regulator. Endocr Rev. 2003; 24(1):78-90. doi: 10.1210/er.2002-0012

[176] Handschin C, Spiegelman BM. Peroxisome proliferator- activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 2006; 27(7):728-735. doi: 10.1210/er.2006-0037

[177] Zhang L, Zhang Y, Chang X, Zhang X. Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis. Cell Death Dis. 2020; 11(4):226. doi: 10.1038/s41419-020-2429-9

[178] Faubion WA, Guicciardi ME, Miyoshi H, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest. 1999; 103(1):137-145. doi: 10.1172/JCI4765

[179] Yu T, Wang L, Lee H, et al. Decreasing mitochondrial fission prevents cholestatic liver injury. J Biol Chem. 2014; 289(49):34074-34088. doi: 10.1074/jbc.M114.588616

[180] Broadbent SD, Ramjeesingh M, Bear CE, Argent BE, Linsdell P, Gray MA. The cystic fibrosis transmembrane conductance regulator is an extracellular chloride sensor. Pflugers Arch. 2015; 467(8):1783-1794. doi: 10.1007/s00424-014-1618-8

[181] García R, Falduti C, Clauzure M, et al. CFTR chloride channel activity modulates the mitochondrial morphology in cultured epithelial cells. Int J Biochem Cell Biol. 2021;135:105976. doi: 10.1016/j.biocel.2021.105976

[182] Chan DC. Fusion and fission: Interlinked processes critical for mitochondrial health. Annu Rev Genet. 2012;46:265-287. doi: 10.1146/annurev-genet-110410-132529

[183] Mishra P, Chan DC.Metabolic regulation of mitochondrial dynamics. J Cell Biol. 2016; 212(4):379-387. doi: 10.1083/jcb.201511036

[184] Youle RJ, van der Bliek AM.Mitochondrial fission, fusion, and stress. Science. 2012; 337(6098):1062-1065. doi: 10.1126/science.1219855

[185] Gilkerson R, De La Torre P, St Vallier S. Mitochondrial OMA1 and OPA1 as gatekeepers of organellar structure/ function and cellular stress response. Front Cell Dev Biol. 2021;9:626117. doi: 10.3389/fcell.2021.626117

[186] Chen Y, Dorn GW 2nd. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013; 340(6131):471-475. doi: 10.1126/science.1231031

[187] Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet. 2009; 18(R2):R169-R176. doi: 10.1093/hmg/ddp326

[188] Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007; 130(3):548-562. doi: 10.1016/j.cell.2007.06.026

[189] Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003; 160(2):189-200. doi: 10.1083/jcb.200211046

[190] Olichon A, Emorine LJ, Descoins E, et al. The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space. FEBS Lett. 2002; 523(1-3):171-176. doi: 10.1016/s0014-5793(02)02985-x

[191] Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin. J Cell Sci. 2001; 114(Pt 5):867-874. doi: 10.1242/jcs.114.5.867

[192] Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science. 2004; 305(5685):858-862. doi: 10.1126/science.1099793

[193] Daste F, Sauvanet C, Bavdek A, et al. The heptad repeat domain 1 of Mitofusin has membrane destabilization function in mitochondrial fusion. EMBO Rep. 2018; 19(6):e43637. doi: 10.15252/embr.201643637

[194] Yan L, Qi Y, Huang X, et al. Structural basis for GTP hydrolysis and conformational change of MFN1 in mediating membrane fusion. Nat Struct Mol Biol. 2018; 25(3):233-243. doi: 10.1038/s41594-018-0034-8

[195] Ishihara N, Eura Y, Mihara K. Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci. 2004; 117(Pt 26):6535-6546. doi: 10.1242/jcs.01565

[196] Tanaka A, Cleland MM, Xu S, et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol. 2010; 191(7):1367-1380. doi: 10.1083/jcb.201007013

[197] Basso V, Marchesan E, Peggion C, et al.Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacol Res. 2018; 138:43-56. doi: 10.1016/j.phrs.2018.09.006

[198] Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007; 178(5):749-755. doi: 10.1083/jcb.200704110

[199] Meeusen S, McCaffery JM, Nunnari J. Mitochondrial fusion intermediates revealed in vitro. Science. 2004; 305(5691):1747-1752. doi: 10.1126/science.1100612

[200] Ban T, Heymann JA, Song Z, Hinshaw JE, Chan DC. OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet. 2010; 19(11):2113-2122. doi: 10.1093/hmg/ddq088

[201] Delettre C, Lenaers G, Griffoin JM, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000; 26(2):207-210. doi: 10.1038/79936

[202] Liesa M, Borda-d’Agua B, Medina-Gómez G, et al. Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta. PLoS One. 2008; 3(10):e3613. doi: 10.1371/journal.pone.0003613

[203] Soriano FX, Liesa M, Bach D, Chan DC, Palacín M, Zorzano A.Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes. 2006; 55(6):1783-1791. doi: 10.2337/db05-0509

[204] Zorzano A. Regulation of mitofusin-2 expression in skeletal muscle. Appl Physiol Nutr Metab. 2009; 34(3):433-439. doi: 10.1139/H09-049

[205] Lee JY, Kapur M, Li M, et al. MFN1 deacetylation activates adaptive mitochondrial fusion and protects metabolically challenged mitochondria. J Cell Sci. 2014; 127(Pt 22):4954-4963. doi: 10.1242/jcs.157321

[206] Pyakurel A, Savoia C, Hess D, Scorrano L. Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis. Mol Cell. 2015; 58(2):244-254. doi: 10.1016/j.molcel.2015.02.021

[207] Dasgupta A, Chen KH, Lima PDA, et al. PINK1-induced phosphorylation of mitofusin 2 at serine 442 causes its proteasomal degradation and promotes cell proliferation in lung cancer and pulmonary arterial hypertension. FASEB J. 2021; 35(8):e21771. doi: 10.1096/fj.202100361R

[208] Leboucher GP, Tsai YC, Yang M, et al.Stress-induced phosphorylation and proteasomal degradation of mitofusin facilitates mitochondrial fragmentation and apoptosis. Mol Cell. 2012; 47(4):547-557. doi: 10.1016/j.molcel.2012.05.041

[209] Li J, Dang X, Franco A, Dorn GW 2nd. Reciprocal regulation of mitofusin 2-mediated mitophagy and mitochondrial fusion by different PINK1 phosphorylation events. Front Cell Dev Biol. 2022;10:868465. doi: 10.3389/fcell.2022.868465

[210] Park YY, Nguyen OT, Kang H, Cho H. MARCH5- mediated quality control on acetylated Mfn1 facilitates mitochondrial homeostasis and cell survival. Cell Death Dis. 2014;5(4):e1172. doi: 10.1038/cddis.2014.142

[211] Sugiura A, Nagashima S, Tokuyama T, et al. MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell. 2013;51(1):20-34. doi: 10.1016/j.molcel.2013.04.023

[212] Yamada T, Ikeda A, Murata D, et al. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1. Nature. 2025;639(8055):776-783. doi: 10.1038/s41586-025-08590-2

[213] Ashraf R, Kumar S. Mfn2-mediated mitochondrial fusion promotes autophagy and suppresses ovarian cancer progression by reducing ROS through AMPK/mTOR/ERK signaling. Cell Mol Life Sci. 2022;79(11):573. doi: 10.1007/s00018-022-04595-6

[214] Pang G, Xie Q, Yao J. Mitofusin 2 inhibits bladder cancer cell proliferation and invasion via the Wnt/β-catenin pathway. Oncol Lett. 2019;18(3):2434-2442. doi: 10.3892/ol.2019.10570

[215] Yu M, Nguyen ND, Huang Y, et al. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. JCI Insight. 2019;5(16):e126915. doi: 10.1172/jci.insight.126915

[216] Dabravolski SA, Nikiforov NG, Zhuravlev AD, Orekhov NA, Mikhaleva LM, Orekhov AN. The role of altered mitochondrial metabolism in thyroid cancer development and mitochondria-targeted thyroid cancer treatment. Int J Mol Sci. 2021;23(1):460. doi: 10.3390/ijms23010460

[217] You MH, Jeon MJ, Kim SR, et al. Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression. Sci Rep. 2021;11(1):2054. doi: 10.1038/s41598-021-81469-0

[218] Zhang Z, Li TE, Chen M, et al. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. Br J Cancer. 2020;122(2):209-220. doi: 10.1038/s41416-019-0658-4

[219] Huang ZJ, Li YJ, Yang J, et al. PTPLAD1 Regulates PHB- Raf interaction to orchestrate epithelial-mesenchymal and mitofusion-fission transitions in colorectal cancer. Int J Biol Sci. 2024;20(6):2202-2218. doi: 10.7150/ijbs.82361

[220] Si L, Fu J, Liu W, et al. Silibinin inhibits migration and invasion of breast cancer MDA-MB-231 cells through induction of mitochondrial fusion. Mol Cell Biochem. 2020;463(1-2):189-201. doi: 10.1007/s11010-019-03640-6

[221] Martinez-Bernabe T, Sastre-Serra J, Ciobu N, Oliver J, Pons DG, Roca P. Estrogen receptor beta (ERβ) maintains mitochondrial network regulating invasiveness in an obesity-related inflammation condition in breast cancer. Antioxidants (Basel). 2021;10(9):1371. doi: 10.3390/antiox10091371

[222] Wang W, Cheng X, Lu J, et al. Mitofusin-2 is a novel direct target of p53. Biochem Biophys Res Commun. 2010;400(4):587-592. doi: 10.1016/j.bbrc.2010.08.108

[223] Ahn SY, Song J, Kim YC, Kim MH, Hyun YM. Mitofusin-2 promotes the epithelial-mesenchymal transition-induced cervical cancer progression. Immune Netw. 2021;21(4):e30. doi: 10.4110/in.2021.21.e30

[224] Ahn SY. Mitofusin-2 enhances cervical cancer progression through Wnt/β-catenin signaling. BMB Rep. 2024; 57(4):194-199. doi: 10.5483/BMBRep.2023-0205

[225] Shukal D, Bhadresha K, Shastri B, Mehta D, Vasavada A, Johar K Sr. Dichloroacetate prevents TGFβ-induced epithelial-mesenchymal transition of retinal pigment epithelial cells. Exp Eye Res. 2020;197:108072. doi: 10.1016/j.exer.2020.108072

[226] Ryu SW, Yoon J, Yim N, Choi K, Choi C. Downregulation of OPA3 is responsible for transforming growth factor- β-induced mitochondrial elongation and F-actin rearrangement in retinal pigment epithelial ARPE-19 cells. PLoS One. 2013;8(5):e63495. doi: 10.1371/journal.pone.0063495

[227] Sun L, Yuan Q, Xu T, et al. Pioglitazone improves mitochondrial function in the remnant kidney and protects against renal fibrosis in 5/6 nephrectomized rats. Front Pharmacol. 2017;8:545. doi: 10.3389/fphar.2017.00545

[228] Chung KP, Hsu CL, Fan LC, et al. Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis. Nat Commun. 2019;10(1):3390. doi: 10.1038/s41467-019-11327-1

[229] Quan Y, Park W, Jin J, Kim W, Park SK, Kang KP. Sirtuin 3 activation by honokiol decreases unilateral ureteral obstruction-induced renal inflammation and fibrosis via regulation of mitochondrial dynamics and the renal NF-κBTGF-β1/Smad signaling pathway. Int J Mol Sci. 2020;21(2):402. doi: 10.3390/ijms21020402

[230] Smith-Cortinez N, van Eunen K, Heegsma J, et al. Simultaneous induction of glycolysis and oxidative phosphorylation during activation of hepatic stellate cells reveals novel mitochondrial targets to treat liver fibrosis. Cells. 2020;9(11):2456. doi: 10.3390/cells9112456

[231] Yapa NMB, Lisnyak V, Reljic B, Ryan MT. Mitochondrial dynamics in health and disease. FEBS Lett. 2021; 595(8):1184-1204. doi: 10.1002/1873-3468.14077

[232] Ren Z, Zhang X, Ding T, et al. Mitochondrial dynamics imbalance: A strategy for promoting viral infection. Front Microbiol. 2020;11:1992. doi: 10.3389/fmicb.2020.01992

[233] Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009; 89(3):799-845. doi: 10.1152/physrev.00030.2008

[234] Sesaki H, Jensen RE. Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol. 1999;147(4):699-706. doi: 10.1083/jcb.147.4.699

[235] Bleazard W, McCaffery JM, King EJ, et al. The dynamin- related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol. 1999;1(5):298-304. doi: 10.1038/13014

[236] Wang Y, Lu M, Xiong L, et al. Drp1-mediated mitochondrial fission promotes renal fibroblast activation and fibrogenesis. Cell Death Dis. 2020;11(1):29. doi: 10.1038/s41419-019-2218-5

[237] Twig G, Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Antioxid Redox Signal. 2011;14(10):1939-1951. doi: 10.1089/ars.2010.3779

[238] Sabouny R, Shutt TE. Reciprocal regulation of mitochondrial fission and fusion. Trends Biochem Sci. 2020;45(7):564-577. doi: 10.1016/j.tibs.2020.03.009

[239] Yoo SM, Jung YK. A molecular approach to mitophagy and mitochondrial dynamics. Mol Cells. 2018;41(1):18-26. doi: 10.14348/molcells.2018.2277

[240] Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433-446. doi: 10.1038/sj.emboj.7601963

[241] Xian H, Liou YC. Functions of outer mitochondrial membrane proteins: Mediating the crosstalk between mitochondrial dynamics and mitophagy. Cell Death Differ. 2021;28(3):827-842. doi: 10.1038/s41418-020-00657-z

[242] Haeussler S, Köhler F, Witting M, et al. Autophagy compensates for defects in mitochondrial dynamics. PLoS Genet. 2020;16(3):e1008638. doi: 10.1371/journal.pgen.1008638

[243] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8(21):2003-2014. doi: 10.3969/j.issn.1673-5374.2013.21.009

[244] Dong Z, Wang X, Wang P, et al. Idiopathic pulmonary fibrosis caused by damaged mitochondria and imbalanced protein homeostasis in alveolar epithelial type II cell. Adv Biol (Weinh). 2025;9(4):e2400297. doi: 10.1002/adbi.202400297

[245] Gao L, Peng L, Wang J, Zhang JH, Xia Y. Mitochondrial stress: A key role of neuroinflammation in stroke. J Neuroinflammation. 2024;21(1):44. doi: 10.1186/s12974-024-03033-7

[246] Adam-Vizi V, Starkov AA. Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis. 2010;20 Suppl 2(Suppl 2):S413-S426. doi: 10.3233/JAD-2010-100465

[247] Torres AK, Fleischhart V, Inestrosa NC. Mitochondrial unfolded protein response (UPRmt): What we know thus far. Front Cell Dev Biol. 2024;12:1405393. doi: 10.3389/fcell.2024.1405393

[248] O’Malley J, Kumar R, Inigo J, Yadava N, Chandra D. Mitochondrial stress response and cancer. Trends Cancer. 2020;6(8):688-701. doi: 10.1016/j.trecan.2020.04.009

[249] Shpilka T, Haynes CM. The mitochondrial UPR: Mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol. 2018;19(2):109-120. doi: 10.1038/nrm.2017.110

[250] Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease. Science. 2020;368(6489):eaat5314. doi: 10.1126/science.aat5314

[251] Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM. The integrated stress response. EMBO Rep. 2016;17(10):1374-1395. doi: 10.15252/embr.201642195

[252] Wu NN, Zhang Y, Ren J. Mitophagy, mitochondrial dynamics, and homeostasis in cardiovascular aging. Oxid Med Cell Longev. 2019;2019:9825061. doi: 10.1155/2019/9825061

[253] Burman JL, Pickles S, Wang C, et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol. 2017;216(10):3231-3247. doi: 10.1083/jcb.201612106

[254] Uoselis L, Nguyen TN, Lazarou M. Mitochondrial degradation: Mitophagy and beyond. Mol Cell. 2023;83(19):3404-3420. doi: 10.1016/j.molcel.2023.08.021

[255] Zhu J, Wang KZ, Chu CT. After the banquet: Mitochondrial biogenesis, mitophagy, and cell survival. Autophagy. 2013;9(11):1663-1676. doi: 10.4161/auto.24135

[256] Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis and clearance: A balancing act. FEBS J. 2017;284(2):183-195. doi: 10.1111/febs.13820

[257] Abu Shelbayeh O, Arroum T, Morris S, Busch KB. PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants (Basel). 2023;12(5):1075. doi: 10.3390/antiox12051075

[258] Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69-84. doi: 10.1042/bse0470069

[259] Choi Y, Seo H, Cho M, et al. Rutin inhibits DRP1-mediated mitochondrial fission and prevents ethanol-induced hepatotoxicity in HepG2 cells and zebrafish. Anim Cells Syst (Seoul). 2021;25(1):74-81. doi: 10.1080/19768354.2021.1882565

[260] Lee DG, Min JS, Lee HS, Lee DS. Isoliquiritigenin attenuates glutamate-induced mitochondrial fission via calcineurin- mediated Drp1 dephosphorylation in HT22 hippocampal neuron cells. Neurotoxicology. 2018;68:133-141. doi: 10.1016/j.neuro.2018.07.011

[261] Kunnumakkara AB, Bordoloi D, Harsha C, Banik K, Gupta SC, Aggarwal BB. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin Sci (Lond). 2017;131(15):1781-1799. doi: 10.1042/CS20160935

[262] Zoi V, Galani V, Lianos GD, Voulgaris S, Kyritsis AP, Alexiou GA. The role of curcumin in cancer treatment. Biomedicines. 2021;9(9):1086. doi: 10.3390/biomedicines9091086

[263] Farhood B, Mortezaee K, Goradel NH, et al. Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy. J Cell Physiol. 2019;234(5):5728-5740. doi: 10.1002/jcp.27442

[264] Fadus MC, Lau C, Bikhchandani J, Lynch HT. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. J Tradit Complement Med. 2016;7(3):339-346. doi: 10.1016/j.jtcme.2016.08.002

[265] Aggarwal D, Chaudhary M, Bajaj N, et al. Anti- inflammatory potential of curcumin: From chemistry and mechanistic insight to nanoformulations. Curr Bioact Compd. 2024;20(1):10-20. doi: 10.2174/1573407219666230726164538

[266] Kumari S, Singh P, Dash D, Singh R. Understanding the molecular basis of anti-fibrotic potential of intranasal curcumin and its association with mitochondrial homeostasis in silica-exposed mice. Mitochondrion. 2024;78:101943. doi: 10.1016/j.mito.2024.101943

[267] Cai Y, Huang C, Zhou M, et al. Role of curcumin in the treatment of acute kidney injury: Research challenges and opportunities. Phytomedicine. 2022;104:154306. doi: 10.1016/j.phymed.2022.154306

[268] Ortega-Domínguez B, Aparicio-Trejo OE, García-Arroyo FE, et al. Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic. Food Chem Toxicol. 2017;107(Pt A):373-385. doi: 10.1016/j.fct.2017.07.018

[269] Aparicio-Trejo OE, Tapia E, Molina-Jijón E, et al. Curcumin prevents mitochondrial dynamics disturbances in early 5/6 nephrectomy: Relation to oxidative stress and mitochondrial bioenergetics. Biofactors. 2017;43(2):293-310. doi: 10.1002/biof.1338

[270] Torcasio R, Gallo Cantafio ME, Veneziano C, et al. Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity. J Transl Med. 2024;22(1):208. doi: 10.1186/s12967-024-05013-0

[271] Zhang H, Li Y, Liu Y. An updated review of the pharmacological effects and potential mechanisms of hederagenin and its derivatives. Front Pharmacol. 2024;15:1374264. doi: 10.3389/fphar.2024.1374264

[272] Su F, Sui X, Xu J, et al. Hederagenin suppresses ovarian cancer via targeting mitochondrial fission through dynamin- related protein 1. Eur J Pharmacol. 2024;963:176188. doi: 10.1016/j.ejphar.2023.176188

[273] Li F, Li D, Tang S, et al. Quercetin protects H9c2 cardiomyocytes against oxygen-glucose deprivation/ reoxygenation-induced oxidative stress and mitochondrial apoptosis by regulating the ERK1/2/DRP1 signaling pathway. Evid Based Complement Alternat Med. 2021;2021:7522175. doi: 10.1155/2021/7522175

[274] Chen C, Huang J, Shen J, Bai Q. Quercetin improves endothelial insulin sensitivity in obese mice by inhibiting Drp1 phosphorylation at serine 616 and mitochondrial fragmentation. Acta Biochim Biophys Sin (Shanghai). 2019;51(12):1250-1257. doi: 10.1093/abbs/gmz127

[275] Wu J, Chen H, Qin J, et al. Baicalin improves cardiac outcome and survival by suppressing Drp1-mediated mitochondrial fission after cardiac arrest-induced myocardial damage. Oxid Med Cell Longev. 2021;2021:8865762. doi: 10.1155/2021/8865762

[276] Jiang C, Zhang J, Xie H, et al. Baicalein suppresses lipopolysaccharide-induced acute lung injury by regulating Drp1-dependent mitochondrial fission of macrophages. Biomed Pharmacother. 2022;145:112408. doi: 10.1016/j.biopha.2021.112408

[277] Wang XL, Feng ST, Wang YT, et al. Mangiferin, a natural glucoxilxanthone, inhibits mitochondrial dynamin- related protein 1 and relieves aberrant mitophagic proteins in mice model of Parkinson’s disease. Phytomedicine. 2022;104:154281. doi: 10.1016/j.phymed.2022.154281

[278] Peng K, Tao Y, Zhang J, et al. Resveratrol regulates mitochondrial biogenesis and fission/fusion to attenuate rotenone-induced neurotoxicity. Oxid Med Cell Longev. 2016;2016:6705621. doi: 10.1155/2016/6705621

[279] Chen Q, Ruan D, Shi J, Du D, Bian C. The multifaceted roles of natural products in mitochondrial dysfunction. Front Pharmacol. 2023;14:1093038. doi: 10.3389/fphar.2023.1093038

[280] Rahmani S, Roohbakhsh A, Karimi G. Inhibition of Drp1- dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries. Pharmacol Res. 2023;188:106672. doi: 10.1016/j.phrs.2023.106672

[281] Yue W, Chen Z, Liu H, et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res. 2014;24(4):482-496. doi: 10.1038/cr.2014.20

[282] Zacharioudakis E, Agianian B, Kumar MV, et al. Modulating mitofusins to control mitochondrial function and signaling. Nat Commun. 2022;13(1):3775. doi: 10.1038/s41467-022-31324-1

[283] Ding M, Feng N, Tang D, et al. Melatonin prevents Drp1- mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway. J Pineal Res. 2018;65(2):e12491. doi: 10.1111/jpi.12491

[284] Aminzadeh-Gohari S, Weber DD, Vidali S, Catalano L, Kofler B, Feichtinger RG. From old to new - Repurposing drugs to target mitochondrial energy metabolism in cancer. Semin Cell Dev Biol. 2020;98:211-223. doi: 10.1016/j.semcdb.2019.05.025

[285] Datta S, Sears T, Cortopassi G, Woolard K, Angelastro JM. Repurposing FDA approved drugs inhibiting mitochondrial function for targeting glioma-stem like cells. Biomed Pharmacother. 2021;133:111058. doi: 10.1016/j.biopha.2020.111058

[286] Raali R, Sivakumar N, Vardhan JH, Suresh PK. Targeting mitochondrial dynamics: An in-silico approach for repurposing antifungal drugs in OSCC treatment. J Biomol Struct Dyn. 2024;12:1-14. doi: 10.1080/07391102.2024.2425831

[287] Patel B, Gelat B, Soni M, Rathaur P, Johar SRK. Bioinformatics perspective of drug repurposing. Curr Bioinform. 2024;19(4):e101023221971. doi: 10.2174/0115748936264692230921071504

[288] Feng J, Hu S, Liu K, Sun G, Zhang Y. The role of MicroRNA in the regulation of tumor epithelial-mesenchymal transition. Cells. 2022;11(13):1981. doi: 10.3390/cells11131981

[289] Patel A, Patel P, Mandlik D, et al. Correction: A novel 3-miRNA network regulates tumour progression in oral squamous cell carcinoma. Biomark Res. 2024;12(1):28. doi: 10.1186/s40364-024-00575-z

[290] Cursons J, Pillman KA, Scheer KG, et al. Combinatorial targeting by MicroRNAs Co-ordinates post-transcriptional control of EMT. Cell Syst. 2018;7(1):77-91.e7. doi: 10.1016/j.cels.2018.05.019

[291] Chen Y, Li S, Zhang Y, et al. The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics. Redox Biol. 2021;41:101910. doi: 10.1016/j.redox.2021.101910

[292] Silva-Gomez JA, Galicia-Moreno M, Sandoval-Rodriguez A, et al. Hepatocarcinogenesis prevention by pirfenidone Is PPARγ mediated and involves modification of nuclear NF-kB p65/p50 ratio. Int J Mol Sci. 2021;22(21):11360. doi: 10.3390/ijms222111360

[293] Iwata T, Yoshino I, Yoshida S, et al. A phase II trial evaluating the efficacy and safety of perioperative pirfenidone for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 6711 L (PEOPLE Study). Respir Res. 2016;17(1):90. doi: 10.1186/s12931-016-0398-4

[294] Sakairi Y, Yoshino I, Iwata T, et al. A randomized controlled phase III trial protocol: perioperative pirfenidone therapy in patients with non-small cell lung cancer combined with idiopathic pulmonary fibrosis to confirm the preventative effect against postoperative acute exacerbation: The PIII- PEOPLE study (NEJ034). J Thorac Dis. 2023;15(3):1486-1493. doi: 10.21037/jtd-22-535

[295] Chen C, Zeng B, Xue D, et al. Pirfenidone for the prevention of radiation-induced lung injury in patients with locally advanced oesophageal squamous cell carcinoma: A protocol for a randomised controlled trial. BMJ Open. 2022;12(10):e060619. doi: 10.1136/bmjopen-2021-060619

[296] Yoon HY, Kim H, Bae Y, Song JW. Pirfenidone and risk of lung cancer development in idiopathic pulmonary fibrosis: A nationwide population-based study. Eur Respir J. 2025;65(2):2401484. doi: 10.1183/13993003.01484-2024

[297] Otsubo K, Kishimoto J, Ando M, et al. Nintedanib plus chemotherapy for nonsmall cell lung cancer with idiopathic pulmonary fibrosis: A randomised phase 3 trial. Eur Respir J. 2022;60(6):2200380. doi: 10.1183/13993003.00380-2022

[298] Sanchez-Laorden B, Nieto MA. Antifibrotic drugs as therapeutic tools in resistant melanoma. EMBO Mol Med. 2022;14(3):e15449. doi: 10.15252/emmm.202115449

[299] Diazzi S, Baeri A, Fassy J, et al. Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma. EMBO Mol Med. 2022;14(3):e15295. doi: 10.15252/emmm.202115295