线粒体动力学与内质网应激在肿瘤化疗耐药中的作用机制

doi:10.19803/j.1672-8629.20260249

摘要/Abstract

摘要： 目的探讨线粒体动力学与内质网应激在肿瘤化疗耐药中的作用机制,为研发逆转耐药的临床治疗策略提供参考。方法系统检索国内外相关研究,对线粒体动力学（分裂与融合）关键调控因子及其在耐药中的作用,以及内质网应激未折叠蛋白反应（UPR）3条关键通路（IRE1α、PERK、ATF6）分子机制与化疗耐药关系进行归纳与总结。结果药物治疗是恶性肿瘤的主要治疗手段之一,但耐药性的产生限制了其疗效。线粒体通过动力学重塑调节细胞代谢、氧化磷酸化和凋亡阈值,内质网应激通过激活UPR通路,从而导致耐药。结论线粒体动力学和内质网应激是介导肿瘤化疗耐药的重要机制,二者通过线粒体-内质网接触点（MAMs）存在密切交互作用。靶向线粒体动力学关键蛋白或调控内质网应激信号通路,有望成为逆转肿瘤耐药、提高化疗疗效的新策略。

关键词: 肿瘤, 耐药, 线粒体动力学, 内质网应激, 交互作用, 机制

Abstract: Objective To explore the mechanisms of mitochondrial dynamics and endoplasmic reticulum stress in tumor chemoresistance so as to provide references for the development of clinical strategies for reversing drug resistance. Methods The key regulators of mitochondrial dynamics (fission and fusion) and their roles in drug resistance as well as the relationships between the three key pathways of the unfolded protein response (UPR) in endoplasmic reticulum stress (IRE1α, PERK, and ATF6) and chemoresistance were summarized based on literature review. Results Pharmacotherapy was one of the leading approaches to malignant tumors. However, the therapeutic efficacy was strongly limited by drug resistance. Mitochondria could regulate cellular metabolism, oxidative phosphorylation, and apoptotic thresholds through dynamic remodeling while endoplasmic reticulum stress could activate UPR pathways, collectively contributing to drug resistance. Conclusion Mitochondrial dynamics and endoplasmic reticulum stress are important mechanisms that mediate tumor chemoresistance, with close interactions between the two organelles through mitochondria-associated endoplasmic reticulum membranes (MAMs). Targeting key proteins involved in mitochondrial dynamics or modulating endoplasmic reticulum stress signaling pathways promises to be a novel strategy for reversing tumor drug resistance and improving chemotherapy efficacy.

Key words: Tumor, Drug Resistance, Mitochondrial Dynamics, Endoplasmic Reticulum Stress, Interaction, Mechanism

中图分类号:

高志超, 赵晨光, 樊又宁, 薛文涵, 梁经纬, 王琳, 孟繁浩. 线粒体动力学与内质网应激在肿瘤化疗耐药中的作用机制[J]. 中国药物警戒, 2026, 23(6): 601-606.

GAO Zhichao, ZHAO Chenguang, FAN Youning, XUE Wenhan, LIANG Jingwei, WANG Lin, MENG Fanhao. Molecular Mechanisms of Mitochondrial Dynamics and Endoplasmic Reticulum Stress in Tumor Chemoresistance[J]. Chinese Journal of Pharmacovigilance, 2026, 23(6): 601-606.

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参考文献

[1] BRAY F, LAVERSANNE M, SUNG H, et al.Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] VASAN N, BASELGA J, HYMAN DM.A View on Drug Resistance in Cancer[J]. Nature, 2019, 575(7782): 299-309.
[3] CHAN DC.Mitochondrial Dynamics and Its Involvement in Disease[J]. Annu Rev Pathol, 2020, 15: 235-259.
[4] HETZ C, ZHANG K, KAUFMAN RJ.Mechanisms, Regulation and Functions of the Unfolded Protein Response[J]. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
[5] GIORGI C, MARCHI S, PINTON P. The Machineries, Regulation and Cellular Functions of Mitochondrial Calcium[J]. Nat Rev Mol Cell Biol, 2018, 19(11): 713-730.
[6] SUN P, SHEN Y, YI J.Research Progress of Mitochondrial Dynamics in Endometriosis[J]. Fuer Jiankang Daokan(妇儿健康导刊), 2025, 4(11): 18-21.
[7] LI G, FU X.Research Progress of Mitochondrial Dynamics in the Septic Cardiomyopathy[J]. J Clin Pathol Res(临床与病理杂志), 2017, 37(6): 1300-1303.
[8] TABARA LC, SEGAWA M, PRUDENT J.Molecular Mechanisms of Mitochondrial Dynamics[J]. Nat Rev Mol Cell Biol, 2025, 26(2): 123-146.
[9] MISHRA SR, MISHRA P, SENZPATI PK, et al.Intricate Role of DRP1 and Associated Mitochondrial Fission Signaling in Carcinogenesis and Cancer Progression[J]. Biochim Biophys Acta Rev Cancer, 2025, 1880(6): 189453.
[10] SU X, LIU J, WANG C, et al.Drp1-Mediated Mitochondrial Fission Promotes Glucose Metabolism Reprogramming in Gastric Cancer Cells[J]. Chinese Journal of Gerontology(中国老年学杂志), 2025, 45(13): 3281-3288.
[11] SUN Y, ZANG S, YU W, et al.Effects and Challenges of Pharmacology and Toxicology of Aconitum Diterpenoid Alkaloids[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2025, 22(6): 601-607.
[12] SHEN Q, PAN X, LI J, et al.Decoding Mitochondrial Signaling: Neutrophil-Tumor Cell Crosstalk in Orchestrating Cancer Progression[J]. J Transl Med, 2026, 24(1): 413.
[13] ZHANG Y, SHI C, ZHANG Q, et al.Research Progress in Mitochondrial Dynamics and Cytoskeleton[J]. Mil Med Jnt Log(联勤军事医学), 2024, 38(9): 809-812.
[14] SUN F, FANG M, ZHANG H, et al.Drp1: Focus on Diseases Triggered by the Mitochondrial Pathway[J]. Cell Biochem Biophys, 2024, 82(2): 435-455.
[15] MENG Y, QIU L, ZENG X, et al.Targeting CRL4 Suppresses Chemoresistant Ovarian Cancer Growth by Inducing Mitophagy[J]. Signal Transduct Target Ther, 2022, 7(1): 388.
[16] QUINTANA-CABRERA R, SCORRANO L.Determinants and Outcomes of Mitochondrial Dynamics[J]. Mol Cell, 2023, 83(6): 857-876.
[17] WANG Y, LIU HH, CAO YT, et al.The Role of Mitochondrial Dynamics and Mitophagy in Carcinogenesis, Metastasis and Therapy[J]. Front Cell Dev Biol, 2020, 8: 413.
[18] SONG C, PAN S, ZHANG J, et al.Mitophagy: a Novel Perspective for Insight into Cancer and Cancer Treatment[J]. Cell Prolif, 2022, 55(12): e13327.
[19] XIE L, SHI F, LI Y, et al.Drp1-Dependent Remodeling of Mitochondrial Morphology Triggered by EBV-LMP1 Increases Cisplatin Resistance[J]. Signal Transduct Target Ther, 2020, 5(1): 56.
[20] DU H, XU T, YU S, et al.Mitochondrial Metabolism and Cancer Therapeutic Innovation[J]. Signal Transduct Target Ther, 2025, 10(1): 245.
[21] CHANG JC, CHANG HS, WU YC, et al.Mitochondrial Transplantation Regulates Antitumour Activity, Chemoresistance and Mitochondrial Dynamics in Breast Cancer[J]. J Exp Clin Cancer Res, 2019, 38(1): 30.
[22] JIN P, JIANG J, ZHOU L, et al.Mitochondrial Adaptation in Cancer Drug Resistance: Prevalence, Mechanisms, and Management[J]. J Hematol Oncol, 2022, 15(1): 97.
[23] LIN Q, LI X, MENG F.Drug Resistance Mechanism of Pemetrexed in Non-Small Cell Lung Cancer[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2023, 20(11): 1201-1208.
[24] VAZQUEZ F, LIM JH, CHIM H, et al.PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress[J]. Cancer Cell, 2013, 23(3): 287-301.
[25] HE F, GONG P, ZHAO S, et al. Construction of a Mouse Model of Tunicamycin-Induced Hepatic Endoplasmic Reticulum Stress and Lipid Metabolism Disorders[J/OL]. J Nanjing Agricultural University(南京农业大学), (2025-09-30)[2026-04-20]. https://link.cnki.net/urlid/32.1148.S.20250930.0913.002.
[26] WU J.Molecular Mechanism of CXCL8 on Promoting Malignant Progression of Esophageal Squamous Cell Carcinoma under Endoplasmic Reticulum Stress State[D]. Shijiazhuang: Hebei Medical University, 2024.
[27] SHENG X.The Role and Mechanism of Endoplasmic Reticulum Stress Signaling Network in Disease Prevention and Treatment[C]. Proceedings of the 10th National Toxicology Conference of the Chinese Society of Toxicology(中国毒理学会第十次全国毒理学大会论文集), 2023: 534.
[28] MENG Y.NK-1R Antagonist Mediates Chemotherapy Sensitization and Reversal of Chemotherapy Resistance in Colorectal Cancer Cells through Endoplasmic Reticulum Stress PERK-eIF2α-ATF4 Signaling Axis[D]. Hangzhou: Zhejiang Sci-Tech University, 2021.
[29] BI Y.Mechanism Study of Endoplasmic Reticulum Stress-Related Apoptosis Pathway in Gastric Cancer Drug-Resistant Cells[D]. Tianjin: Tianjin Medical University, 2020.
[30] TENG M, WU T, PRITCHARD KA, et al.The Destructive Cycle in Bronchopulmonary Dysplasia: The Rationale for Systems Pharmacology Therapeutics[J]. Antioxidants(Basel), 2025, 14(7): 844.
[31] HE M, LIU T, ZHU H, et al.Research Progress on the Role of Endoplasmic Reticulum Stress Response in Prostate Cancer[J]. Medical Journal of Wuhan University(武汉大学学报医学版), 2026, 47(4): 496-503.
[32] GUO J, LAI W, MA C, et al.IRE1α and miR-346 Interactively Regulate to Maintain the Intensity of Endoplasmic Reticulum Stress and Promote Cisplatin Resistance in Cervical Cancer Cells[J]. J Practical Medicine(实用医学杂志), 2021, 37(17): 2176-2181.
[33] CHEN X, CUBILLOS-RUIZ JR.Endoplasmic Reticulum Stress Signals in the Tumor and Its Microenvironment[J]. Nat Rev Cancer, 2021, 21(2): 71-88.
[34] LI H, LIU Y, HUANG J, et al.Molecular Mechanism of Buzhong Yiqi Decoction in Regulating Endoplasmic Reticulum Stress via Nrf2/ROS/PERK/CHOP Signaling Pathway to Improve NSCLC Cisplatin Resistance[J]. J Chin Experimental Formulae(中国实验方剂学杂志), 2025, 31(10): 79-89.
[35] XU Y, GUI F, ZHZNG Z, et al.IRE1α-XBP1s Axis Regulates SREBP1-Dependent MRP1 Expression to Promote Chemoresistance in Non-Small Cell Lung Cancer Cells[J]. Thorac Cancer, 2024, 15(29): 2116-2127.
[36] WANG A, SUN G.The Role and Research Progress of Endoplasmic Reticulum Stress in Antitumor Therapy[J]. Chin Pharmacol Bull(中国药理学通报), 2021, 37(12): 1643-1647.
[37] GENG N, LI X, ZHENG X, et al.Brefeldin A Enhances the Effect of Cisplatin on Inhibiting Lung Cancer Cell Proliferation by Regulating the ATF6 Pathway[J]. J Zunyi Medical University(遵义医学院学报), 2018, 41(4): 431-436.
[38] OU C, SONG H, XIE W, et al.In vitro Study on the Regulation of GRP78/IRE1/ATF6 Pathway by Ziyin Mingmu Formula to Improve Retinal Pigment Degeneration[J]. J Beijing Uni Trad Chin Med(北京中医药大学学报), 2024, 47(6): 773-781.
[39] MADDEN E, LOGUE SE, HEALY SJ, et al.The Role of the Unfolded Protein Response in Cancer Progression: from Oncogenesis to Chemoresistance[J]. Biol Cell, 2019, 111(1): 1-17.
[40] WANG Z.The Effect of Glucose Regulated Protein 78 on the Sensitivity of Lung Adenocarcinoma to Gemcitabine Chemotherapy[D]. Jinzhou: Jinzhou Medical University, 2019.
[41] CUBILLOS-RUIZ JR, BETTIGOLE SE, GLIMCHER LH.Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer[J]. Cell, 2017, 168(4): 692-706.
[42] URRA H, DUFEY E, AVRIL T, et al.Endoplasmic Reticulum Stress and the Hallmarks of Cancer[J]. Trends Cancer, 2016, 2(5): 252-262.
[43] LV R, DOU F, CHAI M, et al.Research Progress on the Mechanism of Traditional Chinese Medicine Regulating Mitochondrial Autophagy and Anti-Tumor Effects[J]. Chin Herbal med(中草药), 2025, 56(8): 3005-3013.
[44] HERSEY P, ZHANG XD.Adaptation to ER Stress as a Driver of Malignancy and Resistance to Therapy in Human Melanoma[J]. Pigment Cell Melanoma Res, 2008, 21(3): 358-367.
[45] LUBRANO S, CERVANTES-VILLAGRANA RD, FARAJI F, et al.FAK Inhibition Combined with the RAF-MEk Clamp Avutometinib Overcomes Resistance to Targeted and Immune Therapies in BRAF V600E Melanoma[J]. Cancer Cell, 2025, 43(3): 428-445.
[46] SHI Y, ZHANG B, WANG Y, et al.Doxorubicin-Induced Cardiotoxicity Related to Regulation of Mitochondria-Associated Membranes by PDK4[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2025, 22(8): 863-868.
[47] FERAL K, JAUD M, PHILIPPE C, et al.ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?[J]. Biomolecules, 2021, 11(2): 199.
[48] BUI V, SANTERRE M, SHCHERBIK N, et al.Mitochondria-Associated Membranes(MAMs): Molecular Organization, Cellular Functions, and Their Role in Health and Disease[J]. FEBS Open Bio, 2026, 16(1): 11-24.
[49] OBARA CJ, NIXON-ABELL J, MOORE AS, et al.Motion of VAPB Molecules Reveals ER-Mitochondria Contact Site Subdomains[J]. Nature, 2024, 626(7997): 169-176.
[50] WANG Y, ZHANG Y, JIN Q, et al.The Role of Mitochondria-Associated Endoplasmic Reticulum Membranes(MAMs) in Diabetic Microvascular Complications: a Review[J]. Cell Death Dis, 2025, 17(1): 81.
[51] HUANG C, RADI RH, ARBISER JL.Mitochondrial Metabolism in Melanoma[J]. Cells, 2021, 10(11): 3197.
[52] AN G, PARK J, SONG J, et al.Relevance of the Endoplasmic Reticulum-Mitochondria Axis in Cancer Diagnosis and Therapy[J]. Exp Mol Med, 2024, 56(1): 40-50.
[53] HOU D, LIAO H, HAO S, et al.Curcumin Simultaneously Improves Mitochondrial Dynamics and Myocardial Cell Bioenergy after Sepsis via the SIRT1-DRP1/PGC-1α Pathway[J]. Heliyon, 2024, 10(7): e28501.
[54] FIGUEROA-GONZALEZ G, QUINTAS-GRANADOS L, REYES-HERNANDEZ O, et al, Review of the Anticancer Properties of 6-Shogaol: Mechanisms of Action in Cancer Cells and Future Research Opportunities[J]. Food Sci Nutr, 2024, 12(7): 4513-4533.
[55] JIANG C, SHEN J, WANG C, et al.Mechanism of Aconitine Mediated Neuronal Apoptosis Induced by Mitochondrial Calcium Overload Caused by MCU[J]. Toxicol Lett, 2023, 384: 86-95.
[56] XIAO Y, YU TJ, XU Y, et al.Emerging Therapies in Cancer Metabolism[J]. Cell Metab, 2023, 35(8): 1283-1303.
[57] WAI T, LANGER T.Mitochondrial Dynamics and Metabolic Regulation[J]. Trends Endocrinol Metab, 2016, 27(2): 105-117.
[58] WANG M, KAUFMAN RJ.Protein Misfolding in the Endoplasmic Reticulum as a Conduit to Human Disease[J]. Nature, 2016, 529(7586): 326-335.
[59] ZHANG H, WANG S, WU P, et al.Revealing the Landscape of Targeting Mitochondrial Functions and Behaviors to Overcome Cancer Chemoresistance[J]. J Natl Cancer Cent, 2025, 5(5): 453-473.