端粒对代谢相关脂肪性肝病的调控作用机制及相关靶向治疗

赵一鸣; 吴小梅; 黄敬; 赵琦; 杨梅

doi:10.12449/JCH260626

端粒对代谢相关脂肪性肝病的调控作用机制及相关靶向治疗

DOI: 10.12449/JCH260626

赵一鸣¹,
吴小梅¹,
黄敬²,
赵琦²,
杨梅^3, , ,

1.
贵州中医药大学第二临床医学院，贵阳 550002
2.
贵州中医药大学第二附属医院消化内科，贵阳 550001
3.
贵州中医药大学第二附属医院检验科，贵阳 550001

基金项目:

国家自然科学基金 (82160866);

贵州省科技计划项目 (Guizhou Science and Technology base-ZK （2023） General 433);

贵州省高等学校重点实验室建设项目 (Guizhou Education Technology （2023）017);

贵州省中医药、民族医药科学技术研究课题 (QZYY-2025-182);

2024年贵州中医药大学“青年扬帆计划”项目 (Guizhongyaokehe-QNYFZK （2024） No.12)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：赵一鸣负责选题及撰写论文；吴小梅、黄敬参与查找文献及修改论文；赵琦负责拟定思路；杨梅负责指导撰写文章。

详细信息

通信作者:
杨梅， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

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出版历程
- 收稿日期: 2025-11-02
- 录用日期: 2025-12-09
- 出版日期: 2026-06-25

Regulatory mechanism of telomere in metabolic associated fatty liver disease and related targeted therapies

1.
The Second Clinical Medical School of Guizhou University of Traditional Chinese Medicine，Guiyang 550002，China
2.
Department of Gastroenterology，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China
3.
Department of Clinical Laboratory，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China

Research funding:

National Natural Science Foundation of China (82160866);

Science and Technology Plan Project of Guizhou Province (Guizhou Science and Technology base-ZK （2023） General 433);

Key Laboratory Construction Project of Higher Education in Guizhou Province (Guizhou Education Technology （2023）017);

Guizhou Provincial Scientific and Technological Research Project on Traditional Chinese Medicine and Ethnic Medicine (QZYY-2025-182);

2024 “Youth Sailing Program” Project of Guizhou University of Traditional Chinese Medicine (Guizhongyaokehe-QNYFZK （2024） No.12)

More Information

Corresponding author: YANG Mei， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

摘要

摘要: 代谢相关脂肪性肝病（MAFLD）是全球发病率最高的慢性肝病，其进展与肝纤维化、肝硬化甚至肝细胞癌的发生密切相关，然而目前临床尚缺乏高效的治疗手段。端粒作为染色体末端的保护性结构，其长度缩短与功能异常被证实是调控MAFLD病理进程的关键因素之一。本文系统综述了端粒调控在MAFLD中的核心作用机制，涵盖其在核苷酸代谢、氧化应激、表观遗传调控中的分子功能，以及在肝细胞与肝星状细胞中的病理效应，并进一步探讨端粒作为MAFLD生物标志物与治疗干预靶点的临床前景，以期为完善MAFLD的精准诊疗体系提供理论参考。
- 代谢相关脂肪性肝病 /
- 端粒缩短 /
- 核苷酸代谢 /
- 氧化应激 /
- 表观基因组学
Abstract: Metabolic associated fatty liver disease （MAFLD） is the most prevalent chronic liver disease worldwide， and its progression is closely associated with the development of liver fibrosis， liver cirrhosis， and even hepatocellular carcinoma. However， there is still a lack of effective therapies for MAFLD in clinical practice. Telomere is the protective structure at the end of chromosomes， and telomere shortening and functional impairment have been identified as one of the key factors regulating the pathological progression of MAFLD. This article systematically reviews the core mechanism of action of telomere regulation in MAFLD， including its molecular functions in nucleotide metabolism， oxidative stress， and epigenetic regulation， as well as its pathological effect in hepatocytes and hepatic stellate cells. In addition， this article explores the clinical prospects of telomeres as biomarkers and therapeutic targets for MAFLD， in order to provide a theoretical reference for improving the precise diagnosis and treatment system of MAFLD.
- Metabolic Associated Fatty Liver Disease /
- Telomere Shortening /
- Nucleotide Metabolism /
- Oxidative Stress /
- Epigenomics

HTML全文

注： MAFLD，代谢相关脂肪性肝病；dG，脱氧鸟苷；dT，脱氧胸苷；PNP，嘌呤核苷磷酸化酶；HGPRT，次黄嘌呤-鸟嘌呤磷酸核糖基转移酶；dNTP，脱氧核苷三磷酸；TK1，胸苷激酶1；dTTP，脱氧胸苷三磷酸；ROS，活性氧；p53，肿瘤蛋白p53；DNA，脱氧核糖核酸；SAM，S-腺苷甲硫氨酸；TERT，端粒逆转录酶；HSC，肝星状细胞；SASP，衰老相关分泌表型；NK细胞，自然杀伤细胞。

图 1 端粒调控MAFLD作用机制图

Figure 1. Mechanism diagram of telomere regulation in MAFLD

下载: 全尺寸图片幻灯片

参考文献(68)

[1]	LOOMBA R, WONG VW. Implications of the new nomenclature of steatotic liver disease and definition of metabolic dysfunction-associated steatotic liver disease[J]. Aliment Pharmacol Ther, 2024, 59( 2): 150- 156. DOI: 10.1111/apt.17846.
[2]	ESLAM M, NEWSOME PN, SARIN SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement[J]. J Hepatol, 2020, 73( 1): 202- 209. DOI: 10.1016/j.jhep.2020.03.039.
[3]	MIAO L, TARGHER G, BYRNE CD, et al. Current status and future trends of the global burden of MASLD[J]. Trends Endocrinol Metab, 2024, 35( 8): 697- 707. DOI: 10.1016/j.tem.2024.02.007.
[4]	DANPANICHKUL P, SUPARAN K, PRASITSUMRIT V, et al. Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations[J]. Clin Mol Hepatol, 2025, 31( 1): 74- 89. DOI: 10.3350/cmh.2024.0631.
[5]	SCHNEIDER CV, SCHNEIDER KM, TEUMER A, et al. Association of telomere length with risk of disease and mortality[J]. JAMA Intern Med, 2022, 182( 3): 291- 300. DOI: 10.1001/jamainternmed.2021.7804.
[6]	SHIN HK, PARK JH, YU JH, et al. Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease[J]. Sci Rep, 2021, 11( 1): 18004. DOI: 10.1038/s41598-021-97385-2.
[7]	ARAVINTHAN A, SCARPINI C, TACHTATZIS P, et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease[J]. J Hepatol, 2013, 58( 3): 549- 556. DOI: 10.1016/j.jhep.2012.10.031.
[8]	REVY P, KANNENGIESSER C, BERTUCH AA. Genetics of human telomere biology disorders[J]. Nat Rev Genet, 2023, 24( 2): 86- 108. DOI: 10.1038/s41576-022-00527-z.
[9]	TURNER KJ, VASU V, GRIFFIN DK. Telomere biology and human phenotype[J]. Cells, 2019, 8( 1): 73. DOI: 10.3390/cells8010073.
[10]	TESMER VM, BRENNER KA, NANDAKUMAR J. Human POT1 protects the telomeric ds-ss DNA junction by capping the 5’ end of the chromosome[J]. Science, 2023, 381( 6659): 771- 778. DOI: 10.1126/science.adi2436.
[11]	TAKAI H, ARIA V, BORGES P, et al. CST-polymerase α-primase solves a second telomere end-replication problem[J]. Nature, 2024, 627( 8004): 664- 670. DOI: 10.1038/s41586-024-07137-1.
[12]	ABDULKINA LR, AGABEKIAN IA, VALEEVA LR, et al. Comparative application of terminal restriction fragment analysis tools to large-scale genomic assays[J]. Int J Mol Sci, 2023, 24( 24): 17194. DOI: 10.3390/ijms242417194.
[13]	LIM CJ, CECH TR. Shaping human telomeres: From shelterin and CST complexes to telomeric chromatin organization[J]. Nat Rev Mol Cell Biol, 2021, 22( 4): 283- 298. DOI: 10.1038/s41580-021-00328-y.
[14]	HUANG XQ, HUANG LY, LU JW, et al. The relationship between telomere length and aging-related diseases[J]. Clin Exp Med, 2025, 25( 1): 72. DOI: 10.1007/s10238-025-01608-z.
[15]	SHIM HS, IACONELLI J, SHANG XY, et al. TERT activation targets DNA methylation and multiple aging hallmarks[J]. Cell, 2024, 187( 15): 4030- 4042. e 13. DOI: 10.1016/j.cell.2024.05.048.
[16]	HARLEY CB, FUTCHER AB, GREIDER CW. Telomeres shorten during ageing of human fibroblasts[J]. Nature, 1990, 345( 6274): 458- 460. DOI: 10.1038/345458a0.
[17]	ROSSIELLO F, JURK D, PASSOS JF, et al. Telomere dysfunction in ageing and age-related diseases[J]. Nat Cell Biol, 2022, 24( 2): 135- 147. DOI: 10.1038/s41556-022-00842-x.
[18]	DI MICCO R, KRIZHANOVSKY V, BAKER D, et al. Cellular senescence in ageing: From mechanisms to therapeutic opportunities[J]. Nat Rev Mol Cell Biol, 2021, 22( 2): 75- 95. DOI: 10.1038/s41580-020-00314-w.
[19]	CAO TQ, LIU SM, WANG F, et al. Insufficient telomeric DNA damage response promotes chromosomal instability in aged oocytes[J]. Sci Bull, 2025. DOI: 10.1016/j.scib.2025.08.034.[ Epub ahead of print]
[20]	JALAN-SAKRIKAR N, ANWAR A, YAQOOB U, et al. Telomere dysfunction promotes cholangiocyte senescence and biliary fibrosis in primary sclerosing cholangitis[J]. JCI Insight, 2023, 8( 20): e170320. DOI: 10.1172/jci.insight.170320.
[21]	DU K, UMBAUGH DS, WANG LY, et al. Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction[J]. Nat Commun, 2025, 16( 1): 3038. DOI: 10.1038/s41467-025-57616-w.
[22]	ALARABI M, PAN ZY, ROMERO-GÓMEZ M, et al. Telomere length and mortality in lean MAFLD: The other face of metabolic adaptation[J]. Hepatol Int, 2024, 18( 5): 1448- 1458. DOI: 10.1007/s12072-024-10701-6.
[23]	CHEN C, WANG L. Aging and metabolic dysfunction-associated steatotic liver disease: A bidirectional relationship[J]. Front Med, 2025, 19( 3): 427- 438. DOI: 10.1007/s11684-025-1133-7.
[24]	GU L, ZHU YH, NANDI SP, et al. FBP1 controls liver cancer evolution from senescent MASH hepatocytes[J]. Nature, 2025, 637( 8045): 461- 469. DOI: 10.1038/s41586-024-08317-9.
[25]	SUNG JY, KIM JH. Telomere-metabolism-immunity axis in sarcoma: Immune evasion mechanisms and therapeutic strategies[J]. Clin Transl Med, 2025, 15( 10): e70504. DOI: 10.1002/ctm2.70504.
[26]	BAHAT A, MILENKOVIC D, CORS E, et al. Ribonucleotide incorporation into mitochondrial DNA drives inflammation[J]. Nature, 2025, 647( 8090): 726- 734. DOI: 10.1038/s41586-025-09541-7.
[27]	PETERSEN MB, CHHETRI G, SOMYAJIT K. Metabolic control of replisome plasticity in genome surveillance[J]. Trends Cell Biol, 2025, 35( 10): 880- 892. DOI: 10.1016/j.tcb.2025.01.006.
[28]	LI C, STOMA S, LOTTA LA, et al. Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length[J]. Am J Hum Genet, 2020, 106( 3): 389- 404. DOI: 10.1016/j.ajhg.2020.02.006.
[29]	TUMMALA H, WALNE A, BUCCAFUSCA R, et al. Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita[J]. Am J Hum Genet, 2022, 109( 8): 1472- 1483. DOI: 10.1016/j.ajhg.2022.06.014.
[30]	MANNHERZ W, AGARWAL S. Thymidine nucleotide metabolism controls human telomere length[J]. Nat Genet, 2023, 55( 4): 568- 580. DOI: 10.1038/s41588-023-01339-5.
[31]	MANNHERZ W, CROMPTON A, LAMPL N, et al. Metabolic constraint of human telomere length by nucleotide salvage efficiency[J]. Nat Commun, 2025, 16( 1): 3000. DOI: 10.1038/s41467-025-58221-7.
[32]	DONNE R, SAROUL-AINAMA M, CORDIER P, et al. Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD[J]. Dev Cell, 2022, 57( 14): 1728- 1741. e 6. DOI: 10.1016/j.devcel.2022.06.003.
[33]	YANG HQ, CHEN LL, LIU YH. Association of leukocyte telomere length with the risk of digestive diseases: A large-scale cohort study[J]. Chin Med J, 2025, 138( 1): 60- 67. DOI: 10.1097/CM9.0000000000002994.
[34]	ZHANG B, HUANG Y, LI XD. Diets with higher inflammatory and insulinemic potential are associated with shorter relative telomere length[J]. Nutr Res Pract, 2025, 19( 4): 621- 634. DOI: 10.4162/nrp.2025.19.4.621.
[35]	IQBAL MJ, KABEER A, ABBAS Z, et al. Interplay of oxidative stress, cellular communication and signaling pathways in cancer[J]. Cell Commun Signal, 2024, 22( 1): 7. DOI: 10.1186/s12964-023-01398-5.
[36]	HUO ZY, CHEN YJ, HUANG YT, et al. Long-term prognosis of lean MASLD: Evidence from three population-based prospective cohorts[J]. Gut, 2025: gutjnl-gu2025- 336127. DOI: 10.1136/gutjnl-2025-336127.
[37]	CASAGRANDE S, HAU M. Telomere attrition: Metabolic regulation and signalling function?[J]. Biol Lett, 2019, 15( 3): 20180885. DOI: 10.1098/rsbl.2018.0885.
[38]	KAWANISHI S, OIKAWA S. Mechanism of telomere shortening by oxidative stress[J]. Ann N Y Acad Sci, 2004, 1019: 278- 284. DOI: 10.1196/annals.1297.047.
[39]	KENDELLEN MF, BARRIENTOS KS, COUNTER CM. POT1 association with TRF2 regulates telomere length[J]. Mol Cell Biol, 2009, 29( 20): 5611- 5619. DOI: 10.1128/MCB.00286-09.
[40]	LI YL, CHANG JT, LEE LY, et al. GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway[J]. Oncotarget, 2017, 8( 1): 1508- 1528. DOI: 10.18632/oncotarget.13649.
[41]	BARNES RP, de ROSA M, THOSAR SA, et al. Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening[J]. Nat Struct Mol Biol, 2022, 29( 7): 639- 652. DOI: 10.1038/s41594-022-00790-y.
[42]	SAHIN E, COLLA S, LIESA M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise[J]. Nature, 2011, 470( 7334): 359- 365. DOI: 10.1038/nature09787.
[43]	YOUNOSSI Z, ANSTEE QM, MARIETTI M, et al. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2018, 15( 1): 11- 20. DOI: 10.1038/nrgastro.2017.109.
[44]	LI YY. Modern epigenetics methods in biological research[J]. Methods, 2021, 187: 104- 113. DOI: 10.1016/j.ymeth.2020.06.022.
[45]	LU SC, MATO JM. S-adenosylmethionine in liver health, injury, and cancer[J]. Physiol Rev, 2012, 92( 4): 1515- 1542. DOI: 10.1152/physrev.00047.2011.
[46]	HERNANDEZ-MEZA G, von FELDEN J, GONZALEZ-KOZLOVA EE, et al. DNA methylation profiling of human hepatocarcinogenesis[J]. Hepatology, 2021, 74( 1): 183- 199. DOI: 10.1002/hep.31659.
[47]	ESOPI D, GRAHAM MK, BROSNAN-CASHMAN JA, et al. Pervasive promoter hypermethylation of silenced TERT alleles in human cancers[J]. Cell Oncol, 2020, 43( 5): 847- 861. DOI: 10.1007/s13402-020-00531-7.
[48]	YU F, THIESEN J, STRÄTLING WH. Histone deacetylase-independent transcriptional repression by methyl-CpG-binding protein 2[J]. Nucleic Acids Res, 2000, 28( 10): 2201- 2206. DOI: 10.1093/nar/28.10.2201.
[49]	LEWIS KA, TOLLEFSBOL TO. Regulation of the telomerase reverse transcriptase subunit through epigenetic mechanisms[J]. Front Genet, 2016, 7: 83. DOI: 10.3389/fgene.2016.00083.
[50]	FERNÁNDEZ-RAMOS D, LOPITZ-OTSOA F, LU SC, et al. S-adenosylmethionine: A multifaceted regulator in cancer pathogenesis and therapy[J]. Cancers, 2025, 17( 3): 535. DOI: 10.3390/cancers17030535.
[51]	CHEN Z, ZHANG XM, DENG MX, et al. Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis[J]. Dis Model Mech, 2025, 18( 6): dmm052313. DOI: 10.1242/dmm.052313.
[52]	HUANG BL, HU XW. Causality of aging hallmarks[J]. Aging Dis, 2025. DOI: 10.14336/AD.2025.0541.[ Epub ahead of print]
[53]	YANG Y, JN-SIMON N, HE YH, et al. A BCL-xL/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice[J]. Nat Aging, 2025, 5( 3): 386- 400. DOI: 10.1038/s43587-025-00811-7.
[54]	DU K, WANG LY, JUN JH, et al. Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress[J]. Nat Aging, 2024, 4( 7): 949- 968. DOI: 10.1038/s43587-024-00652-w.
[55]	DU K, UMBAUGH DS, REN NS, et al. Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting[J]. J Hepatol, 2026, 84( 1): 194- 212. DOI: 10.1016/j.jhep.2025.08.021.
[56]	SANFELIU-REDONDO D, GIBERT-RAMOS A, GRACIA-SANCHO J. Cell senescence in liver diseases: Pathological mechanism and theranostic opportunity[J]. Nat Rev Gastroenterol Hepatol, 2024, 21( 7): 477- 492. DOI: 10.1038/s41575-024-00913-4.
[57]	KIM D, DANPANICHKUL P, WIJARNPREECHA K, et al. Leukocyte telomere shortening in metabolic dysfunction-associated steatotic liver disease and all-cause/cause-specific mortality[J]. Clin Mol Hepatol, 2024, 30( 4): 982- 986. DOI: 10.3350/cmh.2024.0691.
[58]	JURK D, WILSON C, PASSOS JF, et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice[J]. Nat Commun, 2014, 2: 4172. DOI: 10.1038/ncomms5172.
[59]	SCHAFER MJ, WHITE TA, IIJIMA K, et al. Cellular senescence mediates fibrotic pulmonary disease[J]. Nat Commun, 2017, 8: 14532. DOI: 10.1038/ncomms14532.
[60]	TANG LX, LI DK, MA Y, et al. The association between telomere length and non-alcoholic fatty liver disease: A prospective study[J]. BMC Med, 2023, 21( 1): 427. DOI: 10.1186/s12916-023-03136-7.
[61]	WANG HL, LIU ZQ, FAN H, et al. Association between advanced fibrosis and epigenetic age acceleration among individuals with MASLD[J]. J Gastroenterol, 2025, 60( 3): 306- 314. DOI: 10.1007/s00535-024-02181-0.
[62]	TORRES-OTEROS D, PARILLI-MOSER I, LAVERIANO SANTOS EP, et al. Unveiling the impact of peanut consumption on telomere length in young and healthy individuals: Insights from the ARISTOTLE study: A randomized clinical trial[J]. Antioxidants, 2025, 14( 4): 467. DOI: 10.3390/antiox14040467.
[63]	KIRKLAND JL, TCHKONIA T. Senolytic drugs: From discovery to translation[J]. J Intern Med, 2020, 288( 5): 518- 536. DOI: 10.1111/joim.13141.
[64]	BLAGOSKLONNY MV. Rapamycin for longevity: Opinion article[J]. Aging, 2019, 11( 19): 8048- 8067. DOI: 10.18632/aging.102355.
[65]	KULKARNI AS, GUBBI S, BARZILAI N. Benefits of metformin in attenuating the hallmarks of aging[J]. Cell Metab, 2020, 32( 1): 15- 30. DOI: 10.1016/j.cmet.2020.04.001.
[66]	GORGOULIS V, ADAMS PD, ALIMONTI A, et al. Cellular senescence: Defining a path forward[J]. Cell, 2019, 179( 4): 813- 827. DOI: 10.1016/j.cell.2019.10.005.
[67]	BERNARDES DE JESUS B, SCHNEEBERGER K, VERA E, et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence[J]. Aging Cell, 2011, 10( 4): 604- 621. DOI: 10.1111/j.1474-9726.2011.00700.x.
[68]	RUDOLPH KL, CHANG S, LEE HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice[J]. Cell, 1999, 96( 5): 701- 712. DOI: 10.1016/s0092-8674(00)80580-2.