分子伴侣介导的自噬在消化系统疾病的研究进展
Research Progress on Chaperone Mediated Autophagy in Digestive System Diseases
DOI: 10.12677/acm.2025.151135, PDF,    科研立项经费支持
作者: 李忠标*:青岛大学青岛医学院,山东 青岛;宋志超#:淄博市第一医院肛肠外科,山东 淄博
关键词: 分子伴侣介导的自噬消化系统疾病溶酶体相关膜蛋白2AChaperone Mediated Autophagy Digestive System Diseases LAMP2A
摘要: 自噬通过溶酶体分解和循环利用细胞成分,促进细胞质量控制和能量代谢。作为自噬的一种形式,分子伴侣介导的自噬(chaperone-mediated autophagy, CMA)选择性降解细胞内含有KFERQ五肽的受损或异常蛋白,在维持细胞稳态中具有核心作用。近期研究表明,CMA通过调控脂质代谢、细胞周期和氧化应激等途径,在消化系统疾病中发挥重要功能。作为CMA标志物的溶酶体相关膜蛋白2A (lysosomal-associated membrane protein 2A, LAMP2A)有望成为诊断、预后及治疗消化系统疾病的潜在靶点。本文总结了CMA在肝癌、胃肠肿瘤、脂肪性肝病及炎性肠病等方面的研究进展,为相关疾病的临床诊疗提供新的视角。
Abstract: Autophagy promotes cellular quality control and energy metabolism by degrading and recycling essential cellular components via lysosomes. As a form of autophagy, Chaperone mediated autophagy (CMA) selectively degrades damaged or dysfunctional proteins containing the KFERQ motif within the cell, playing a central role in maintaining cellular homeostasis. Recent studies indicate that CMA regulates critical processes such as cell cycle, oxidative stress, and lipid metabolism, significantly influencing digestive system diseases. Lysosomal-associated membrane protein 2A (LAMP2A), a CMA marker, holds promise as a potential target for diagnosis, prognosis, and therapy. This review highlights CMA research progress in liver cancer, gastrointestinal tumors, fatty liver disease, and inflammatory bowel diseases, offering new perspectives for clinical management.
文章引用:李忠标, 宋志超. 分子伴侣介导的自噬在消化系统疾病的研究进展[J]. 临床医学进展, 2025, 15(1): 1010-1018. https://doi.org/10.12677/acm.2025.151135

参考文献

[1] Sadeghloo, Z., Nabavi-Rad, A., Zali, M.R., Klionsky, D.J. and Yadegar, A. (2024) The Interplay between Probiotics and Host Autophagy: Mechanisms of Action and Emerging Insights. Autophagy. [Google Scholar] [CrossRef] [PubMed]
[2] Yao, R. and Shen, J. (2023) Chaperone‐Mediated Autophagy: Molecular Mechanisms, Biological Functions, and Diseases. MedComm, 4, e347. [Google Scholar] [CrossRef] [PubMed]
[3] Mastoridou, E.M., Goussia, A.C., Kanavaros, P. and Charchanti, A.V. (2023) Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets. International Journal of Molecular Sciences, 24, Article 15891. [Google Scholar] [CrossRef] [PubMed]
[4] Hubert, V., Weiss, S., Rees, A.J. and Kain, R. (2022) Modulating Chaperone-Mediated Autophagy and Its Clinical Applications in Cancer. Cells, 11, Article 2562. [Google Scholar] [CrossRef] [PubMed]
[5] Dice, J.F., Walker, C.D., Byrne, B. and Cardiel, A. (1978) General Characteristics of Protein Degradation in Diabetes and Starvation. Proceedings of the National Academy of Sciences of the United States of America, 75, 2093-2097. [Google Scholar] [CrossRef] [PubMed]
[6] Le, S., Fu, X., Pang, M., Zhou, Y., Yin, G., Zhang, J., et al. (2022) The Antioxidative Role of Chaperone-Mediated Autophagy as a Downstream Regulator of Oxidative Stress in Human Diseases. Technology in Cancer Research & Treatment, 21, 1-15. [Google Scholar] [CrossRef] [PubMed]
[7] Zhu, L., He, S., Huang, L., Ren, D., Nie, T., Tao, K., et al. (2022) Chaperone‐Mediated Autophagy Degrades Keap1 and Promotes Nrf2‐Mediated Antioxidative Response. Aging Cell, 21, e13616. [Google Scholar] [CrossRef] [PubMed]
[8] Huang, J. and Wang, J. (2024) Selective Protein Degradation through Chaperone-Mediated Autophagy: Implications for Cellular Homeostasis and Disease (Review). Molecular Medicine Reports, 31, Article No. 13. [Google Scholar] [CrossRef] [PubMed]
[9] Filali-Mouncef, Y., Hunter, C., Roccio, F., Zagkou, S., Dupont, N., Primard, C., et al. (2021) The Ménage À Trois of Autophagy, Lipid Droplets and Liver Disease. Autophagy, 18, 50-72. [Google Scholar] [CrossRef] [PubMed]
[10] Yang, M., Luo, S., Chen, W., Zhao, L. and Wang, X. (2023) Chaperone-Mediated Autophagy: A Potential Target for Metabolic Diseases. Current Medicinal Chemistry, 30, 1887-1899. [Google Scholar] [CrossRef] [PubMed]
[11] Park, C., Suh, Y. and Cuervo, A.M. (2015) Regulated Degradation of Chk1 by Chaperone-Mediated Autophagy in Response to DNA Damage. Nature Communications, 6, Article No. 6823. [Google Scholar] [CrossRef] [PubMed]
[12] Andrade-Tomaz, M., de Souza, I., Rocha, C.R.R. and Gomes, L.R. (2020) The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer. Cells, 9, Article 2140. [Google Scholar] [CrossRef] [PubMed]
[13] Ding, Z., Fu, X., Shi, Y., Zhou, J., Peng, Y., Liu, W., et al. (2016) Lamp2a Is Required for Tumor Growth and Promotes Tumor Recurrence of Hepatocellular Carcinoma. International Journal of Oncology, 49, 2367-2376. [Google Scholar] [CrossRef] [PubMed]
[14] Desideri, E., Castelli, S., Dorard, C., Toifl, S., Grazi, G.L., Ciriolo, M.R., et al. (2022) Impaired Degradation of YAP1 and IL6ST by Chaperone-Mediated Autophagy Promotes Proliferation and Migration of Normal and Hepatocellular Carcinoma Cells. Autophagy, 19, 152-162. [Google Scholar] [CrossRef] [PubMed]
[15] Chava, S., Lee, C., Aydin, Y., Chandra, P.K., Dash, A., Chedid, M., et al. (2017) Chaperone-Mediated Autophagy Compensates for Impaired Macroautophagy in the Cirrhotic Liver to Promote Hepatocellular Carcinoma. Oncotarget, 8, 40019-40036. [Google Scholar] [CrossRef] [PubMed]
[16] Wu, J., Guo, J., Shi, J., Wang, H., Li, L., Guo, B., et al. (2017) CMA Down-Regulates P53 Expression through Degradation of HMGB1 Protein to Inhibit Irradiation-Triggered Apoptosis in Hepatocellular Carcinoma. World Journal of Gastroenterology, 23, 2308-2317. [Google Scholar] [CrossRef] [PubMed]
[17] Guo, B., Li, L., Guo, J., Liu, A., Wu, J., Wang, H., et al. (2017) M2 Tumor-Associated Macrophages Produce Interleukin-17 to Suppress Oxaliplatin-Induced Apoptosis in Hepatocellular Carcinoma. Oncotarget, 8, 44465-44476. [Google Scholar] [CrossRef] [PubMed]
[18] Liao, Y., Yang, Y., Pan, D., Ding, Y., Zhang, H., Ye, Y., et al. (2021) HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia. Cancers, 13, Article 243. [Google Scholar] [CrossRef] [PubMed]
[19] Wei, S., Li, W., Liu, Y., Gao, D., Pan, J., Gu, C., et al. (2013) Disturbance of Autophagy-Lysosome Signaling Molecule Expression in Human Gastric Adenocarcinoma. Oncology Letters, 7, 635-640. [Google Scholar] [CrossRef] [PubMed]
[20] Zhou, J., Yang, J., Fan, X., Hu, S., Zhou, F., Dong, J., et al. (2016) Chaperone-Mediated Autophagy Regulates Proliferation by Targeting RND3 in Gastric Cancer. Autophagy, 12, 515-528. [Google Scholar] [CrossRef] [PubMed]
[21] Zhu, Y., Zhou, J., Xia, H., Chen, X., Qiu, M., Huang, J., et al. (2014) The Rho GTPase Rhoe Is a P53-Regulated Candidate Tumor Suppressor in Cancer Cells. International Journal of Oncology, 44, 896-904. [Google Scholar] [CrossRef] [PubMed]
[22] Yoon, J., Brezden-Masley, C. and Streutker, C.J. (2021) Autophagic Heterogeneity in Gastric Adenocarcinoma. Frontiers in Oncology, 11, Article 555614. [Google Scholar] [CrossRef] [PubMed]
[23] Zhang, S., Hu, B., You, Y., Yang, Z., Liu, L., Tang, H., et al. (2018) Sorting Nexin 10 Acts as a Tumor Suppressor in Tumorigenesis and Progression of Colorectal Cancer through Regulating Chaperone Mediated Autophagy Degradation of P21Cip1/WAF1. Cancer Letters, 419, 116-127. [Google Scholar] [CrossRef] [PubMed]
[24] Le, Y., Zhang, S., Ni, J., You, Y., Luo, K., Yu, Y., et al. (2018) Sorting Nexin 10 Controls mTOR Activation through Regulating Amino-Acid Metabolism in Colorectal Cancer. Cell Death & Disease, 9, Article No. 666. [Google Scholar] [CrossRef] [PubMed]
[25] Wang, M., Zhang, Z., Chen, M., Lv, Y., Tian, S., Meng, F., et al. (2023) FDW028, a Novel FUT8 Inhibitor, Impels Lysosomal Proteolysis of B7-H3 via Chaperone-Mediated Autophagy Pathway and Exhibits Potent Efficacy against Metastatic Colorectal Cancer. Cell Death & Disease, 14, Article No. 495. [Google Scholar] [CrossRef] [PubMed]
[26] Xuan, Y., Zhao, S., Xiao, X., Xiang, L. and Zheng, H. (2021) Inhibition of Chaperonemediated Autophagy Reduces Tumor Growth and Metastasis and Promotes Drug Sensitivity in Colorectal Cancer. Molecular Medicine Reports, 23, Article No. 360. [Google Scholar] [CrossRef] [PubMed]
[27] Du, C., Huang, D., Peng, Y., Yao, Y., Zhao, Y., Yang, Y., et al. (2017) 5-Fluorouracil Targets Histone Acetyltransferases P300/CBP in the Treatment of Colorectal Cancer. Cancer Letters, 400, 183-193. [Google Scholar] [CrossRef] [PubMed]
[28] Shi, Z., Yang, S., Shen, C., Shao, J., Zhou, F., Liu, H., et al. (2024) LAMP2A Regulates Cisplatin Resistance in Colorectal Cancer through Mediating Autophagy. Journal of Cancer Research and Clinical Oncology, 150, Article No. 242. [Google Scholar] [CrossRef] [PubMed]
[29] Chen, R., Zhang, Y., Ge, Y., He, C., Wu, Z., Wang, J., et al. (2023) LAMP2A Overexpression in Colorectal Cancer Promotes Cell Growth and Glycolysis via Chaperone-Mediated Autophagy. Oncology Letters, 27, Article No. 33. [Google Scholar] [CrossRef] [PubMed]
[30] Zheng, Y., Wu, C., Yang, J., Zhao, Y., Jia, H., Xue, M., et al. (2020) Insulin-like Growth Factor 1-Induced Enolase 2 Deacetylation by HDAC3 Promotes Metastasis of Pancreatic Cancer. Signal Transduction and Targeted Therapy, 5, Article No. 53. [Google Scholar] [CrossRef] [PubMed]
[31] Xue, N., Lai, F., Du, T., Ji, M., Liu, D., Yan, C., et al. (2019) Chaperone-Mediated Autophagy Degradation of IGF-1Rβ Induced by NVP-AUY922 in Pancreatic Cancer. Cellular and Molecular Life Sciences, 76, 3433-3447. [Google Scholar] [CrossRef] [PubMed]
[32] Ma, S.Y., Sun, K.S., Zhang, M., Zhou, X., Zheng, X.H., Tian, S.Y., et al. (2020) Disruption of Plin5 Degradation by CMA Causes Lipid Homeostasis Imbalance in NAFLD. Liver International, 40, 2427-2438. [Google Scholar] [CrossRef] [PubMed]
[33] Zhang, Y., Li, Y., Liu, Y., Wang, H., Chen, Y., Zhang, B., et al. (2023) Alcoholic Setdb1 Suppression Promotes Hepatosteatosis in Mice by Strengthening Plin2. Metabolism, 146, Article ID: 155656. [Google Scholar] [CrossRef] [PubMed]
[34] Younossi, Z.M. (2019) Non-Alcoholic Fatty Liver Disease—A Global Public Health Perspective. Journal of Hepatology, 70, 531-544. [Google Scholar] [CrossRef] [PubMed]
[35] Choi, Y., Yun, S.H., Yu, J., Mun, Y., Lee, W., Park, C.J., et al. (2023) Chaperone-Mediated Autophagy Dysregulation during Aging Impairs Hepatic Fatty Acid Oxidation via Accumulation of NCoR1. Molecular Metabolism, 76, Article ID: 101784. [Google Scholar] [CrossRef] [PubMed]
[36] Angelini, G., Castagneto Gissey, L., Del Corpo, G., Giordano, C., Cerbelli, B., Severino, A., et al. (2019) New Insight into the Mechanisms of Ectopic Fat Deposition Improvement after Bariatric Surgery. Scientific Reports, 9, Article No. 17315. [Google Scholar] [CrossRef] [PubMed]
[37] You, Y., Li, W., Zhang, S., Hu, B., Li, Y., Li, H., et al. (2018) SNX10 Mediates Alcohol-Induced Liver Injury and Steatosis by Regulating the Activation of Chaperone-Mediated Autophagy. Journal of Hepatology, 69, 129-141. [Google Scholar] [CrossRef] [PubMed]
[38] Lee, W., Kim, H.Y., Choi, Y., Jung, S., Nam, Y.A., Zhang, Y., et al. (2022) SNX10-Mediated Degradation of LAMP2A by Nsaids Inhibits Chaperone-Mediated Autophagy and Induces Hepatic Lipid Accumulation. Theranostics, 12, 2351-2369. [Google Scholar] [CrossRef] [PubMed]
[39] Chandwaskar, R., Dalal, R., Gupta, S., Sharma, A., Parashar, D., Kashyap, V.K., et al. (2024) Dysregulation of T Cell Response in the Pathogenesis of Inflammatory Bowel Disease. Scandinavian Journal of Immunology, 100, e13412. [Google Scholar] [CrossRef] [PubMed]
[40] Valdor, R., Mocholi, E., Botbol, Y., Guerrero-Ros, I., Chandra, D., Koga, H., et al. (2014) Chaperone-Mediated Autophagy Regulates T Cell Responses through Targeted Degradation of Negative Regulators of T Cell Activation. Nature Immunology, 15, 1046-1054. [Google Scholar] [CrossRef] [PubMed]
[41] Retnakumar, S.V., Geesala, R., Bretin, A., Tourneur-Marsille, J., Ogier-Denis, E., Maretzky, T., et al. (2022) Targeting the Endo-Lysosomal Autophagy Pathway to Treat Inflammatory Bowel Diseases. Journal of Autoimmunity, 128, Article ID: 102814. [Google Scholar] [CrossRef] [PubMed]
[42] Wu, K., Liu, Y., Shao, S., Song, W., Chen, X., Dong, Y., et al. (2023) The Microglial Innate Immune Receptors TREM-1 and TREM-2 in the Anterior Cingulate Cortex (ACC) Drive Visceral Hypersensitivity and Depressive-Like Behaviors Following DSS-Induced Colitis. Brain, Behavior, and Immunity, 112, 96-117. [Google Scholar] [CrossRef] [PubMed]
[43] Kökten, T., Gibot, S., Lepage, P., D’Alessio, S., Hablot, J., Ndiaye, N., et al. (2017) TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice. Journal of Crohns and Colitis, 12, 230-244. [Google Scholar] [CrossRef] [PubMed]
[44] Cicchinelli, S., Gemma, S., Pignataro, G., Piccioni, A., Ojetti, V., Gasbarrini, A., et al. (2024) Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators. Pharmaceuticals, 17, Article 490. [Google Scholar] [CrossRef] [PubMed]
[45] Rahmani, F., Asgharzadeh, F., Avan, A., Barneh, F., Parizadeh, M.R., Ferns, G.A., et al. (2020) RETRACTED: Rigosertib Potently Protects against Colitis-Associated Intestinal Fibrosis and Inflammation by Regulating PI3K/AKT and NF-κB Signaling Pathways. Life Sciences, 249, Article ID: 117470. [Google Scholar] [CrossRef] [PubMed]
[46] Tang, J., Zhan, M., Yin, Q., Zhou, C., Wang, C., Wo, L., et al. (2017) Impaired P65 Degradation by Decreased Chaperone-Mediated Autophagy Activity Facilitates Epithelial-to-Mesenchymal Transition. Oncogenesis, 6, e387-e387. [Google Scholar] [CrossRef] [PubMed]
[47] Iyer, S., Enman, M., Sahay, P. and Dudeja, V. (2024) Novel Therapeutics to Treat Chronic Pancreatitis: Targeting Pancreatic Stellate Cells and Macrophages. Expert Review of Gastroenterology & Hepatology, 18, 171-183. [Google Scholar] [CrossRef] [PubMed]
[48] Ren, Y., Cui, Q., Zhang, J., Liu, W., Xu, M., Lv, Y., et al. (2021) Milk Fat Globule-EGF Factor 8 Alleviates Pancreatic Fibrosis by Inhibiting ER Stress-Induced Chaperone-Mediated Autophagy in Mice. Frontiers in Pharmacology, 12, Article 707259. [Google Scholar] [CrossRef] [PubMed]