نشریه فیزیولوژی ورزش و فعالیت بدنی

نشریه فیزیولوژی ورزش و فعالیت بدنی

تعامل میان فعالیت ورزشی و RNAهای غیرکدکننده در NAFLD: یافته‌های بیوانفورماتیکی و تحلیل شبکه‌های تنظیمی

نوع مقاله : مقاله مروری

نویسندگان
گروه فیزیولوژی ورزشی، دانشکدة علوم ورزشی، دانشگاه اصفهان، اصفهان، ایران
چکیده
بیماری کبد چرب غیرالکلی (NAFLD) وابسته به اختلالات سوخت‌وسازی، رژیم‌های غذایی پرچرب و سبک زندگی کم‌تحرک است و به التهاب مزمن، فیبروز کبدی و افزایش خطر ابتلا به سیروز و سرطان کبد منجر می‌شود. با توجه به محدودیت‌های درمانی دارویی، فعالیت ورزشی به‌عنوان رویکردی ایمن و در دسترس، نقش کلیدی و برجسته‌ای در بهبود لیپوژنز، کاهش التهاب و بهبود عملکرد میتوکندری ایفا می‌کند. هدف این پژوهش مروری-بیوانفورماتیکی، بررسی تعاملات و برهمکنش بین فعالیت ورزشی و RNAهای غیرکدکننده (miRNA، lncRNA و circRNA) در زمینة کبد چرب غیرالکلی، شناسایی ncRNAهای تعدیل‌شده توسط فعالیت ورزشی و بازسازی شبکه‌های تنظیمی رقابتی (ceRNA) وابسته به سوخت‌وساز لیپید، التهاب و بیوژنز میتوکندری است. برای دستیابی به این هدف، داده‌های برگرفته از روش‌های حیوانی (رژیم پرچرب با/بدون مداخلة ورزشی) از GEO (GSE239729 و GSE226132) بازیابی شد، سپس جست‌وجوی نظام‌مند در پایگاه‌های دادة PubMed، Scopus، Web of Science و Google Scholar از سال ۲۰۱۹ تا ۲۰۲۵ با استفاده از کلیدواژه‌های استاندارد انجام شد. پیش‌پردازش و هنجارسازی داده‌ها در محیط R (نسخة ۴.۵.۰) با بستة DESeq2صورت گرفت و تمرکز بر ncRNAها با آستانه‌های |log2FC| ≥2 و FDR < 05/0 بود. انوتیشن از منابع Ensembl، NONCODE، LNCipedia، circBase و circAtlas اخذ شد؛ پیش‌بینی اهداف miRNA از TargetScan و miRWalk، تعاملات circRNA-miRNA از starBase استخراج شده و شبکه‌های ceRNA در Cytoscape (نسخة ۳.۱۰.۱) بازسازی شد. غنی‌سازی عملکردی (GO/KEGG) نیز با ابزارهای clusterProfiler و DAVID انجام پذیرفت. یافته‌های ادغام‌شده از مرور ادبیات و بازتحلیل داده‌ها نشان داد که فعالیت ورزشی به‌طور پیوسته بیان miR-34a را کاهش و miR-122 را افزایش می‌دهد؛ در lncRNAها، بیان MALAT1 و HOTAIR کاهش می‌یابد و در circRNAها، circRNA_002581 کاهش و circScd1 افزایش می‌یابد. شبکه‌های ceRNA بیشتر محورهای AMPK،SIRT1/PGC-1α و PPARα را هدف قرار می‌دهند و با کاهش لیپوژنز (↓SREBP1/FASN)، تقویت اکسایش اسیدهای چرب (↑CPT1/FAO)، مهار التهاب (↓NF-KB/TNF-α) و تعدیل پیام‌رسانی TGF-β همخوانی دارند. همسانی الگوها بین دو مجموعه داده، پایداری پاسخ ncRNA-محور به فعالیت ورزشی را تأیید و تحلیل حساسیت با آستانه‌های ملایم‌تر نیز یافته‌های کلیدی و برجسته‌ای را حفظ کرد. به‌طور خلاصه، فعالیت ورزشی از طریق بازتنظیم هماهنگ ncRNAها، معماری شبکه‌های ژنی وابسته به سوخت‌وساز، التهاب و عملکرد میتوکندری را در کبد چرب غیرالکلی بازآرایی می‌کند. این پژوهش، از طریق ادغام یافته‌های پیشینة پژوهشی و بازتحلیل RNA-Seq، چارچوبی عملی-مفهومی برای هدف‌گیری ncRNAها، توسعة نشانگرهای زیستی وابسته به پاسخ به فعالیت ورزشی و طراحی مداخلات RNA-محور مقلد تأثیرات فعالیت ورزشی فراهم می‌آورد. با ادغام مرور نظام‌مند و بازتحلیل داده‌های موجود و بازسازی شبکه‌های ceRNA، نشان داده شد تأثیر فعالیت ورزشی بیشتر از محورها‌ی AMPK، SIRT1/PGC-1α و PPARα میانجی‌گری می‌شود و با الگوهای ncRNA (miR-34a↓، miR-122↑، MALAT1/HOTAIR↓، circScd1↑) همراستاست. این نقشة شبکه‌ای، کاربرد بالینی روشن دارد: 1. نشانگرهای زیستی پاسخ به ورزش، 2. مداخلات RNA-محورِ ( مقلد ورزش‌) با هدف‌گیری این محورها، برای بهینه‌سازی درمان و بهبود نتایج سوخت‌وسازی/التهابی در کبد چرب غیرالکلی.
کلیدواژه‌ها
موضوعات

عنوان مقاله English

The crosstalk between exercise and ncRNAs in NAFLD: bioinformatic evidence and regulatory network analysis

نویسندگان English

Zahra Asheghi
Sayed Mohammad Marandi
Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
چکیده English

Non-alcoholic fatty liver disease (NAFLD) is linked to metabolic dysfunction, high-fat diets, and physical inactivity, culminating in chronic inflammation, hepatic fibrosis, and increased risk of cirrhosis and hepatocellular carcinoma. Given the limitations of pharmacotherapy, exercise represents a safe, accessible intervention that can attenuate lipogenesis, suppress inflammation, and enhance mitochondrial function. This review-plus-bioinformatic study interrogated the crosstalk between exercise and non-coding RNAs (ncRNAs)—microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—in NAFLD, with the goals of identifying exercise-modulated ncRNAs and reconstructing competitive endogenous RNA (ceRNA) networks governing lipid metabolism, inflammation, and bioenergetics. We first retrieved murine high-fat diet (HFD) liver datasets with and without exercise from GEO (GSE239729, GSE226132), then conducted a systematic literature search of PubMed, Scopus, Web of Science, and Google Scholar (2019–2025) using standard keywords. RNA-Seq preprocessing and normalization were performed in R (v4.5.0) with DESeq2; ncRNAs were prioritized using |log₂FC| ≥ 2 and FDR < 0.05. Annotations were drawn from Ensembl, NONCODE, LNCipedia, circBase, and circAtlas; miRNA targets from TargetScan and miRWalk; circRNA–miRNA interactions from starBase. ceRNA networks were reconstructed in Cytoscape (v3.10.1), and functional enrichment (GO/KEGG) was conducted with clusterProfiler and DAVID. Integrated evidence from the literature and reanalysis showed that exercise consistently downregulates miR-34a and the lncRNAs MALAT1/HOTAIR, while upregulating miR-122 and circScd1 and decreasing circRNA_002581. The resulting ceRNA programs converge on AMPK, SIRT1/PGC-1α, and PPARα axes, aligning with reduced lipogenesis (↓SREBP1/FASN), enhanced fatty-acid oxidation (↑CPT1/FAO), dampened inflammation (↓NF-κB/TNF-α), and modulation of TGF-β signaling. Concordant patterns across both datasets support a robust, exercise-driven ncRNA response; sensitivity analyses with more permissive thresholds preserved the key signals. In sum, exercise reprograms NAFLD liver through coordinated ncRNA regulation that reshapes gene networks controlling metabolism, inflammation, and mitochondrial function. By integrating systematic evidence with RNA-Seq reanalysis and ceRNA modeling, we outline a practical framework for (i) ncRNA-based biomarkers of exercise response, and (ii) RNA-directed “exercise-mimetic” interventions targeting AMPK/SIRT1/PPARα to optimize therapy and improve metabolic/inflammatory outcomes in NAFLD.

کلیدواژه‌ها English

Exercise
Non-coding RNAs (ncRNAs)
Non-alcoholic fatty liver disease (NAFLD)
Transcriptomic analysis
Gene regulatory networks
1. Younossi, Z.M., et al., The global epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among patients with type 2 diabetes. Clinical Gastroenterology and Hepatology, 2024. 22(10): p. 1999–2010. e8.. DOI: 10.1016/j.cgh.2024.03.006 2. Spremović Rađenović, S., et al., Prevalence, risk factors, and pathophysiology of nonalcoholic fatty liver disease (NAFLD) in women with polycystic ovary syndrome (PCOS). Biomedicines, 2022. 10(1): p. 131.. DOI: 10.3390/biomedicines10010131 3. Semmler, G., et al., Diet and exercise in NAFLD/NASH: beyond the obvious. Liver International, 2021. 41(10): p. 2249–2268.. DOI: 10.1111/liv.15024 4. Zhang, C.-K., Z.-Z. Wang, and F.-H. Li, Long-term aerobic exercise enhances liver health: miRNA regulation and oxidative stress alleviation. Biochemical and Biophysical Research Communications, 2025. 759: p. 151677.. DOI: 10.1016/j.bbrc.2025.151677 5. Zou, Y., et al., Transcriptomic profiling of long non-coding RNAs and messenger RNAs in the liver of mice during Toxoplasma gondii infection. Parasites & vectors, 2024. 17(1): p. 20.. DOI: 10.1186/s13071-023-06053-z 6. Abubakar, M., et al., Non-coding RNA-mediated gene regulation in cardiovascular disorders: current insights and future directions. Journal of Cardiovascular Translational Research, 2024. 17(4): p. 739–767. DOI: 10.1007/s12265-023-10469-4. 7. Shin, J.-J., et al., Roles of lncRNAs in NF-κB-Mediated macrophage inflammation and their implications in the pathogenesis of human diseases. International Journal of Molecular Sciences, 2024. 25(5): p. 2670. DOI: 10.3390/ijms25052670. 8. Li, C., et al., Regulatory mechanisms of long non-coding RNAs on mitochondrial function in congestive heart failure. Non-coding RNA Research, 2024. 9(1): p. 178–184.. DOI: 10.1016/j.ncrna.2023.11.007 9. Wu, B., et al., Aerobic exercise promotes the expression of ATGL and attenuates inflammation to improve hepatic steatosis via lncRNA SRA. Scientific Reports, 2022. 12(1): p. 5370..DOI: 10.1038/s41598-022-09174-0 10. Varabyou, A., S.L. Salzberg, and M. Pertea, Effects of transcriptional noise on estimates of gene and transcript expression in RNA sequencing experiments. Genome research, 2021. 31(2): p. 301–308..DOI: 10.1101/gr.266213.120 11. Klapproth, C., et al., Common features in lncRNA annotation and classification: a survey. Non-coding RNA, 2021. 7(4): p. 77. DOI: 10.3390/ncrna7040077 12. Mattick, J.S., et al., Long non-coding RNAs: definitions, functions, challenges and recommendations. Nature reviews Molecular cell biology, 2023. 24(6): p. 430–447.. DOI: 10.1038/s41580-022-00566-8 13. Statello, L., et al., Gene regulation by long non-coding RNAs and its biological functions. Nature reviews Molecular cell biology, 2021. 22(2): p. 96–118.. DOI: 10.1038/s41580-020-00315-9 14. Studniarek, C., S. Egloff, and S. Murphy, Noncoding RNAs set the stage for RNA polymerase II transcription. Trends in Genetics, 2021. 37(3): p. 279–291. DOI: 10.1016/j.tig.2020.09.013 15. Pisignano, G. and M. Ladomery, Post-transcriptional regulation through long non-coding rnas (lncrnas). 2021, MDPI. p. 29.. DOI: 10.3390/ncrna7020029 16. Grammatikakis, I. and A. Lal, Significance of lncRNA abundance to function. Mammalian Genome, 2022. 33(2): p. 271–280. DOI: 10.1007/s00335-021-09901-4 17. Zhang, S., et al., Screening of bovine tissue-specific expressed genes and identification of genetic variation within an adipose tissue-specific lncRNA gene. Frontiers in Veterinary Science, 2022. 9: p. 887520.. DOI: 10.3389/fvets.2022.887520 18. Camilleri-Robles, C., et al., Genomic and functional conservation of lncRNAs: lessons from flies. Mammalian Genome, 2022. 33(2): p. 328–342.. DOI: 10.1007/s00335-021-09939-4 19. Brandt, A. and F. Kopp, Long Noncoding RNAs in Diet-Induced Metabolic Diseases. International Journal of Molecular Sciences, 2024. 25(11): p. 5678.. DOI: 10.3390/ijms25115678 20. Ji, M., et al., Naringenin prevents oxidative stress and inflammation in LPS-induced liver injury through the regulation of LncRNA-mRNA in male mice. Molecules, 2022. 28(1): p. 198..DOI: 10.3390/molecules28010198 21. Zhu, S.-F., et al., Research progress of lncRNA and miRNA in hepatic ischemia-reperfusion injury. Hepatobiliary & Pancreatic Diseases International, 2023. 22(1): p. 45–53..DOI: 10.1016/j.hbpd.2022.07.008 22. Zou, D., et al., LncRNA MEG3 up-regulates SIRT6 by ubiquitinating EZH2 and alleviates nonalcoholic fatty liver disease. Cell Death Discovery, 2022. 8(1): p. 103.. DOI: 10.1038/s41420-022-00889-7 23. Moradzad, M., et al., TMAO promotes metabolic dysfunction-associated fatty liver disease (MAFLD) development through long-non coding RNA-highly upregulated liver cancer (HULC). Journal of Diabetes & Metabolic Disorders, 2025. 24(1): p. 1–11.. DOI: 10.1007/s40200-025-01605-9 24. Shi, N., et al., The impact and role of identified long noncoding RNAs in nonalcoholic fatty liver disease: A narrative review. Journal of Clinical Laboratory Analysis, 2023. 37(11-12): p. e24943..DOI: 10.1002/jcla.24943 25. Mukherjee, A.G., et al., Exploring the regulatory role of ncRNA in NAFLD: a particular focus on PPARs. Cells, 2022. 11(24): p. 3959.. DOI: 10.3390/cells11243959 26. Fei, Q., et al., The Impact of Aerobic and Anaerobic Exercise Interventions on the Management and Outcomes of Non-Alcoholic Fatty Liver Disease. Physiological Research, 2024. 73(5): p. 671.. DOI: 10.33549/physiolres.935244 27. Zhang, Y., et al., Long-Term Aerobic Exercise Enhances Hepatoprotection in MAFLD by Modulating Exosomal miR-324 via ROCK1. Metabolites, 2024. 14(12): p. 692.. DOI: 10.3390/metabo14120692 28. Hu, J., X. Miao, and L.-H. Yu, Long Non-Coding RNAs in Diabetic Cardiomyopathy: Potential Function as Biomarkers and Therapeutic Targets of Exercise Training. Journal of Cardiovascular Translational Research, 2025: p. 1–17.. DOI: 10.1007/s12265-024-10586-8 29. Pino-de la Fuente, F., et al., Exercise regulation of hepatic lipid droplet metabolism. Life Sciences, 2022. 298: p. 120522.. DOI: 10.1016/j.lfs.2022.120522 30. Shen, Z., et al., Prediction of Back-splicing sites for CircRNA formation based on convolutional neural networks. BMC genomics, 2022. 23(1): p. 581. DOI: 10.1186/s12864-022-08820-1. 31. Wang, P., et al., The function and regulation network mechanism of circRNA in liver diseases. Cancer Cell International, 2022. 22(1): p. 141.. DOI: 10.1186/s12935-022-02559-1 32. Yang, L., J.E. Wilusz, and L.-L. Chen, Biogenesis and regulatory roles of circular RNAs. Annual review of cell and developmental biology, 2022. 38(1): p. 263–289.. DOI: 10.1146/annurev-cellbio-120420-125117 33. Chodurska, B. and T. Kunej, Long Non-Coding RNAs in Humans: Classification, Genomic Organization and Function. Non-coding RNA Research, 2025.. DOI: 10.1016/j.ncrna.2025.01.004 34. Ma, B., et al., Mechanisms of circRNA/lncRNA-miRNA interactions and applications in disease and drug research. Biomedicine & Pharmacotherapy, 2023. 162: p. 114672.. DOI: 10.1016/j.biopha.2023.114672 35. Zheng, S., et al., CircRNA—protein interactions in muscle development and diseases. International journal of molecular sciences, 2021. 22(6): p. 3262.. DOI: 10.3390/ijms22063262 36. Zheng, M., et al., Expression profile and N6-methyadenosine modification of circular RNA analysis in MAFLD. BMC gastroenterology, 2025. 25(1): p. 162.. DOI: 10.1186/s12876-025-03722-4 37. Yepmo, M., et al., Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Frontiers in Endocrinology, 2022. 13: p. 1035159..DOI: 10.3389/fendo.2022.1035159 38. Li, L.-P., et al., Oxidative stress-induced circSOD2 inhibits osteogenesis through sponging miR-29b in metabolic-associated fatty liver disease. World Journal of Gastroenterology, 2025. 31(9): p. 98027.. DOI: 10.3748/wjg.v31.i9.98027 39. Qian, G. and N. Morral, Role of non-coding RNAs on liver metabolism and NAFLD pathogenesis. Human molecular genetics, 2022. 31(R1): p. R4–R21.. DOI: 10.1093/hmg/ddac088 40. Cao, J., et al., Identification of mitochondrial function and programmed cell death associated key biomarkers and the circRNA-miRNA-mRNA regulatory network in systemic lupus erythematosus. Frontiers in Molecular Biosciences, 2025. 12: p. 1586294.. DOI: 10.3389/fmolb.2025.1586294 41. Wang, Y., et al., A read-through circular RNA RCRIN inhibits metabolic dysfunction-associated steatotic liver disease. Journal of Hepatology, 2025. 82(6): p. 1068–1079. DOI: 10.1016/j.jhep.2024.11.052 42. Zeng, Q., et al., Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance. RNA biology, 2024. 21(1): p. 65–79. DOI: 10.1080/15476286.2023.2290769 43. Shao, J., et al., Interference of a mammalian circRNA regulates lipid metabolism reprogramming by targeting miR-24-3p/Igf2/PI3K-AKT-mTOR and Igf2bp2/Ucp1 axis. Cellular and Molecular Life Sciences, 2023. 80(9): p. 252. DOI: 10.1007/s00018-023-04899-1 44. Wang, L., et al., Exercise-induced circular RNA circUtrn is required for cardiac physiological hypertrophy and prevents myocardial ischaemia–reperfusion injury. Cardiovascular research, 2023. 119(16): p. 2638–2652.. DOI: 10.1093/cvr/cvad161 45. Zaiou, M., Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease. World journal of gastroenterology, 2022. 28(35): p. 5111.. DOI: 10.3748/wjg.v28.i35.5111 46. Yu, G., et al., Circular RNAs: Rising stars in lipid metabolism and lipid disorders. Journal of cellular physiology, 2021. 236(7): p. 4797–4806.. DOI: 10.1002/jcp.30200 47. Zhong, G., Y. Lin, and Z. Huang, Identification of a novel circRNA–miRNA–mRNA regulatory axis in hepatocellular carcinoma based on bioinformatics analysis. Scientific reports, 2023. 13(1): p. 3728.. DOI: 10.1038/s41598-023-30567-2 48. Chen, L.-L. and V.N. Kim, Small and long non-coding RNAs: Past, present, and future. Cell, 2024. 187(23): p. 6451–6485.. DOI: 10.1016/j.cell.2024.10.024 49. Joshi, M., et al., Small RNAs, spermatogenesis, and male infertility: a decade of retrospect. Reproductive Biology and Endocrinology, 2023. 21(1): p. 106.. DOI: 10.1186/s12958-023-01155-w 50. Iwakawa, H.-o. and Y. Tomari, Life of RISC: Formation, action, and degradation of RNA-induced silencing complex. Molecular cell, 2022. 82(1): p. 30–43.. DOI: 10.1016/j.molcel.2021.11.026 51. Kim, H., Y.-Y. Lee, and V.N. Kim, The biogenesis and regulation of animal microRNAs. Nature Reviews Molecular Cell Biology, 2025. 26(4): p. 276–296.. DOI: 10.1038/s41580-024-00805-0 52. Zheng, H., et al., A computational modeling of pri-miRNA expression. Plos one, 2024. 19(1): p. e0290768.. DOI: 10.1371/journal.pone.0290768 53 Khadgi, B. and Y. Nam, Effects of METTL3-METTL14 on primary microRNA processing by Drosha- DGCR8. bioRxiv, 2024: p. 2024.10. 15.618347.. DOI: 10.1101/2024.10.15.618347 54. Li, H., et al., Prognostic significance of exportin-5 in hepatocellular carcinoma. World Journal of Gastrointestinal Oncology, 2024. 16(7): p. 3069.. DOI: 10.4251/wjgo.v16.i7.3069 55. Goel, H. and A. Goel, MicroRNA and Rare Human Diseases. Genes, 2024. 15(10): p. 1243. 56. Liu, F., et al., Long non-coding RNA SNHG6 couples cholesterol sensing with mTORC1 activation in hepatocellular carcinoma. Nature metabolism, 2022. 4(8): p. 1022–1040. DOI: 10.1038/s42255-022-00616-7 57. Zhu, Y., et al., Therapeutic effects of microRNAs on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review and meta-analysis. International journal of molecular sciences, 2023. 24(11): p. 9168.. DOI: 10.3390/ijms24119168 58. Tobaruela-Resola, A.L., et al., Circulating miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p as potential predictive biomarkers for Metabolic Dysfunction-Associated Steatotic Liver Disease assessment. Journal of physiology and biochemistry, 2024: p. 1–14.. DOI: 10.1007/s13105-024-01037- 59. Shan, W., et al., Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell death & disease, 2015. 6(7): p. e1833–e1833.. DOI: 10.1038/cddis.2015.196 60. Latief, U., et al., Micro RNAs as emerging therapeutic targets in liver diseases. Current Protein and Peptide Science, 2022. 23(6): p. 369–383.. DOI: 10.2174/1389203723666220721122240 61. Guo, X., et al., MiRNA-122 contributes to the effect of exercise on non-alcoholic fatty liver. Chinese Journal of Tissue Engineering Research, 2024. 28(2): p. 272.. doi: 10.12307/2023.475 62. Delfan, M., et al., High-intensity interval training improves cardiac function by miR-206 dependent HSP60 induction in diabetic rats. Frontiers in Cardiovascular Medicine, 2022. 9: p. 927956..DOI: 10.3389/fcvm.2022.927956 63. Dos Santos, J.A.C., et al., Physical exercise and the functions of microRNAs. Life sciences, 2022. 304: p. 120723.. DOI: 10.1016/j.lfs.2022.120723 64. Panico, A., et al., The influence of lifestyle factors on miRNA expression and signal pathways: a review. Epigenomics, 2021. 13(2): p. 145–164.. DOI: 10.2217/epi-2020- 289 65. Elazazy, O., et al., Long non-coding RNAs and rheumatoid arthritis: pathogenesis and clinical implications. Pathology-Research and Practice, 2023. 246: p. 154512.. DOI: 10.1016/j.prp.2023.154512 66. Tang, Z., et al., The role of competing endogenous RNA network in the development of hepatocellular carcinoma: potential therapeutic targets. Frontiers in Cell and Developmental Biology, 2024. 12: p. 1341999. DOI: 10.3389/fcell.2024.1341999 67. Zeng, Q., et al., LncRNA and circRNA in patients with non-alcoholic fatty liver disease: a systematic review. Biomolecules, 2023. 13(3): p. 560.. DOI: 10.3390/biom13030560 68. Yonis, N., et al., Cracking the code: lncRNA-miRNA-mRNA integrated network analysis unveiling lncRNAs as promising non-invasive NAFLD biomarkers toward precision diagnosis. Computational Biology and Chemistry, 2025. 115: p. 108325.. DOI: 10.1016/j.compbiolchem.2024.108325 69. Zaiou, M., Peroxisome proliferator-activated receptor-γ as a target and regulator of epigenetic mechanisms in nonalcoholic fatty liver disease. Cells, 2023. 12(8): p. 1205. DOI: 10.3390/cells12081205 70. Shabgah, A.G., et al., A comprehensive review of long non-coding RNAs in the pathogenesis and development of non-alcoholic fatty liver disease. Nutrition & Metabolism, 2021. 18(1): p. 22. DOI: 10.1186/s12986-021-00552-5 71. Zeng, X., et al., Circular RNA as an epigenetic regulator in chronic liver diseases. Cells, 2021. 10(8): p. 1945.. DOI: 10.3390/cells10081945 72. Wang, S., J. Li, and Y. Zhao, Construction and analysis of a network of exercise-induced mitochondria-related non-coding RNA in the regulation of diabetic cardiomyopathy. Plos one, 2024. 19(3): p. e0297848.. DOI: 10.1371/journal.pone.0297848 73. Zhao, W., et al., Exercise improves endothelial function via the lncRNA MALAT1/miR‐320a axis in obese children and adolescents. Cardiology Research and Practice, 2021. 2021(1): p. 8840698.. DOI: 10.1155/2021/8840698 74. Ramezani, M., et al., A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathology-Research and Practice, 2023. 251: p. 154809.. DOI: 10.1016/j.prp.2023.154809 75. Yoshitomi, R., et al., Regulatory effect of epigallocatechin-3-O-gallate on circular RNA expression in mouse liver. The Journal of Nutritional Biochemistry, 2024. 124: p. 109506.. DOI: 10.1016/j.jnutbio. 023.109506 76. Wu, L.-F., et al., Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2024. 327(4): p. G485–G498.. DOI: 10.1152/ajpgi.00255.2023 77. Yang, Y.-b., et al., Identification of a Novel Ferroptosis‐Related Gene Prediction Model for Clinical Prognosis and Immunotherapy of Colorectal Cancer. Disease Markers, 2021. 2021(1): p. 4846683..DOI: 10.1155/2021/4846683 78. Hochreuter, M.Y., et al., MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives. Molecular metabolism, 2022. 65: p. 101581.. DOI: 10.1016/j.molmet.2022.101581 79. Tang, S., Y. Geng, and Q. Lin, The role of mitophagy in metabolic diseases and its exercise intervention. Frontiers in Physiology, 2024. 15: p. 1339128.. DOI: 10.3389/fphys.2024.1339128 80. Ferro, A., et al., Extracellular vesicles as delivery vehicles for non-coding RNAs: potential biomarkers for chronic liver diseases. Biomolecules, 2024. 14(3): p. 277.. DOI: 10.3390/biom14030277 81. Tang, Q. and A. Khvorova, RNAi-based drug design: considerations and future directions. Nature Reviews Drug Discovery, 2024. 23(5): p. 341–364.. DOI: 10.1038/s41573-024-00912-9 82. Cao, X., et al., ncRNADrug: a database for validated and predicted ncRNAs associated with drug resistance and targeted by drugs. Nucleic Acids Research, 2024. 52(D1): p. D1393–D1399..DOI: 10.1093/nar/gkad1042 83. Suksangrat, T., P. Phannasil, and S. Jitrapakdee, miRNA regulation of glucose and lipid metabolism in relation to diabetes and non-alcoholic fatty liver disease. Reviews on biomarker studies of metabolic and metabolism-related disorders, 2019: p. 129–148.. DOI: 10.1007/978-3-030-12668-1_7 84. Atic, A.I., et al., Circulating miRNAs associated with nonalcoholic fatty liver disease. American Journal of Physiology-Cell Physiology, 2023. 324(2): p. C588–C602. DOI: 10.1152/ajpcell.00253.2022 85. Aghaei, S.M. and S.M. Hosseini, Inflammation-related miRNAs in obesity, CVD, and NAFLD. Cytokine, 2024. 182: p. 156724.. DOI: 10.1016/j.cyto.2024.156724 86. Anwar, A.A., N. Jalan-Sakrikar, and R.C. Huebert. LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology. in Seminars in liver disease. 2024. Thieme Medical Publishers, Inc. • DOI: 10.1055/a-2490-1921 87. Wade, H., et al., Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis. eGastroenterology, 2024. 2(4).. DOI: 10.1136/egastro-2024-100115 88. Xie, Y., et al., Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism. Frontiers in Genetics, 2022. 13: p. 884037.. DOI: 10.3389/fgene.2022.884037 89. Zhang, J., et al., The effects of exercise on epigenetic modifications: focus on DNA methylation, histone modifications and non-coding RNAs. Human Cell, 2024. 37(4): p. 887–903.. DOI: 10.1007/s13577-024-01057-y 90. Qin, F., et al., The effects of exercise on microRNA expression profiling in adipose tissue macrophages of mice. Frontiers in Immunology, 2024. 15: p. 1412621.. DOI: 10.3389/fimmu.2024.1412621 91. Soltanieh, S.K., et al., Long Non-Coding RNAs in Non-Alcoholic Fatty Liver Disease; Friends or Foes? Cell Biochemistry and Biophysics, 2025. 83(1): p. 279–294.. DOI: 10.1007/s12013-024-01555-8 92. Ma, X., et al., Physical exercise: a promising treatment against organ fibrosis. International Journal of Molecular Sciences, 2025. 26(1): p. 343.. DOI: 10.3390/ijms26010343 93. Lou, J., et al., Exercise promotes angiogenesis by enhancing endothelial cell fatty acid utilization via liver-derived extracellular vesicle miR-122-5p. Journal of Sport and Health Science, 2022. 11(4): p. 495–508.. DOI: 10.1016/j.jshs.2021.09.009 94. Wu, B., et al., Aerobic exercise improves hepatic steatosis by modulating miR-34a-mediated PPARα/SIRT1-AMPK signaling pathway. 2023.. DOI: 10.1371/journal.pone.0333872 95. Marroncini, G., et al., Gut–liver–pancreas axis crosstalk in health and disease: from the role of microbial metabolites to innovative microbiota manipulating strategies. Biomedicines, 2024. 12(7): p. 1398.. DOI: 10.3390/biomedicines12071398 96. Jiang, C., et al., Comparative transcriptomics analyses in livers of mice, humans, and humanized mice define human-specific gene networks. Cells, 2020. 9(12): p. 2566.. DOI: 10.3390/cells9122566 97. Huppertz, I. and A.C. Mullen, Function Over Form: Defining Evolutionarily Conserved Long Noncoding RNAs Regulating Hepatic Metabolism. Gastroenterology, 2025. DOI: 10.1053/j.gastro.2025.04.008. 98. Zhang, Y., et al., Protective effect of exercise on metabolic dysfunction-associated fatty liver disease: Potential epigenetic mechanisms. International Journal of Molecular Medicine, 2025. 56(4): p. 146. DOI: 10.3892/ijmm.2025.5587

  • تاریخ دریافت 23 تیر 1404
  • تاریخ بازنگری 02 مهر 1404
  • تاریخ پذیرش 14 مهر 1404
  • تاریخ اولین انتشار 14 مهر 1404
  • تاریخ انتشار 01 فروردین 1405