{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:09:59Z","timestamp":1793815799250,"version":"4.6.1"},"reference-count":129,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science and Technology Research Project of the Jiangxi Provincial Department of Education","award":["GJJ2401828"],"award-info":[{"award-number":["GJJ2401828"]}]},{"name":"Science and Technology Research Project of the Jiangxi Provincial Department of Education","award":["GJJ2401834"],"award-info":[{"award-number":["GJJ2401834"]}]},{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"crossref","award":["20242BAB25457"],"award-info":[{"award-number":["20242BAB25457"]}],"id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Age-related osteoporosis is driven in part by senescence-associated rewiring of bone marrow mesenchymal stem cells (MSCs) from osteogenic toward adipogenic fates. Accumulating evidence indicates that epigenetic drift and reduced autophagy are not isolated lesions but are mechanistically coupled through a bidirectional DNA methylation and autophagy axis. Here, we summarize how promoter hypermethylation of genes involved in autophagy and osteogenesis suppresses autophagic flux and osteoblast lineage transcriptional programs. Conversely, autophagy insufficiency reshapes the methylome by limiting methyl donor availability, most notably S-adenosylmethionine (SAM), and by reducing the turnover of key epigenetic regulators, including DNA methyltransferases (DNMTs), ten-eleven translocation (TET) dioxygenases, and histone deacetylases (HDACs). This self-reinforcing circuitry exacerbates mitochondrial dysfunction, oxidative stress, and inflammation driven by the senescence-associated secretory phenotype (SASP), thereby stabilizing adipogenic bias and progressively impairing marrow niche homeostasis and bone remodeling. We further discuss therapeutic strategies to restore balance within this axis, including selective modulation of epigenetic enzymes; activation of AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) signaling with downstream engagement of Unc-51-like autophagy-activating kinase 1 (ULK1) and transcription factor EB (TFEB); targeting sirtuin pathways; mitochondria- and autophagy-supportive natural compounds; and bone-targeted delivery approaches or rational combination regimens.<\/jats:p>","DOI":"10.3390\/biology15030218","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T10:24:36Z","timestamp":1769423076000},"page":"218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The DNA Methylation\u2013Autophagy Axis: A Driver of MSC Fate Imbalance in Skeletal Aging and Osteoporosis"],"prefix":"10.3390","volume":"15","author":[{"given":"Gaojie","family":"Song","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang 332005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingnuan","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang 332005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Xiong","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang 332005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Cheng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Li, S., Liu, G., and Hu, S. (2024). Osteoporosis: Interferon-gamma-mediated bone remodeling in osteoimmunology. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1396122"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bone.2016.01.014","article-title":"Aging alters bone-fat reciprocity by shifting in vivo mesenchymal precursor cell fate towards an adipogenic lineage","volume":"85","author":"Singh","year":"2016","journal-title":"Bone"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1800873","DOI":"10.1002\/advs.201800873","article-title":"Contribution of Mitophagy to Cell-Mediated Mineralization: Revisiting a 50-Year-Old Conundrum","volume":"5","author":"Pei","year":"2018","journal-title":"Adv. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Malava\u0161i\u010d, P., Lojk, J., Lov\u0161in, M.N., and Marc, J. (2025). Recent Advances in Experimental Functional Characterization of GWAS Candidate Genes in Osteoporosis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157237"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e70813","DOI":"10.1111\/jcmm.70813","article-title":"Hedgehog Signalling in Osteogenesis and Bone Metabolism: Molecular Mechanisms, Regulatory Networks and Implications for Skeletal Disease","volume":"29","author":"Njie","year":"2025","journal-title":"J. Cell. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7517","DOI":"10.1111\/jcmm.14620","article-title":"LncRNA HOTAIRM1 promotes osteogenesis by controlling JNK\/AP-1 signalling-mediated RUNX2 expression","volume":"23","author":"Fu","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41419-023-06239-4","article-title":"Mesenchymal stem cells under epigenetic control\u2014The role of epigenetic machinery in fate decision and functional properties","volume":"14","author":"Walewska","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"166975","DOI":"10.1016\/j.bbadis.2023.166975","article-title":"Enhancer-mediated FOXO3 expression promotes MSC adipogenic differentiation by activating autophagy","volume":"1870","author":"Feng","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"129952","DOI":"10.1016\/j.bbagen.2021.129952","article-title":"Trending topics of SIRT1 in tumorigenicity","volume":"1865","author":"Li","year":"2021","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, X., Yu, F., and Ye, L. (2023). Epigenetic control of mesenchymal stem cells orchestrates bone regeneration. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1126787"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Davletgildeeva, A.T., and Kuznetsov, N.A. (2024). The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level. Biomolecules, 14.","DOI":"10.3390\/biom14091117"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s12931-025-03149-1","article-title":"Increased autophagy activity regulated by LC3B gene promoter DNA methylation is associated with progression to active pulmonary tuberculosis disease","volume":"26","author":"Chen","year":"2025","journal-title":"Respir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.14336\/AD.2023.0208","article-title":"Mesenchymal Stem Cell Senescence during Aging: From Mechanisms to Rejuvenation Strategies","volume":"14","author":"Jiang","year":"2023","journal-title":"Aging Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1016\/j.gendis.2022.10.030","article-title":"Epigenetic regulation of mesenchymal stem cell aging through histone modifications","volume":"10","author":"Sun","year":"2023","journal-title":"Genes Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.3724\/abbs.2023060","article-title":"Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation","volume":"55","author":"Yang","year":"2023","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.7150\/ijbs.91480","article-title":"Impaired TFEB-mediated autophagy-lysosome fusion promotes tubular cell cycle G2\/M arrest and renal fibrosis by suppressing ATP6V0C expression and interacting with SNAREs","volume":"20","author":"Ren","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Saul, D., and Kosinsky, R.L. (2021). Epigenetics of Aging and Aging-Associated Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010401"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8836258","DOI":"10.1155\/2020\/8836258","article-title":"Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis","volume":"2020","author":"Wang","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s13577-020-00421-y","article-title":"FOXO3 is targeted by miR-223-3p and promotes osteogenic differentiation of bone marrow mesenchymal stem cells by enhancing autophagy","volume":"34","author":"Long","year":"2021","journal-title":"Hum. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2418023122","DOI":"10.1073\/pnas.2418023122","article-title":"Dnmt3a-mediated hypermethylation of FoxO3 promotes redox imbalance during osteoclastogenesis","volume":"122","author":"Zhang","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.cell.2013.06.041","article-title":"Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A","volume":"154","author":"Sutter","year":"2013","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1080\/15548627.2022.2068267","article-title":"SAMS-1 coordinates HLH-30\/TFEB and PHA-4\/FOXA activities through histone methylation to mediate dietary restriction-induced autophagy and longevity","volume":"19","author":"Lim","year":"2023","journal-title":"Autophagy"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Serefidou, M., Venkatasubramani, A.V., and Imhof, A. (2019). The Impact of One Carbon Metabolism on Histone Methylation. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.00764"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11366","DOI":"10.1038\/s41598-024-62229-2","article-title":"Maternal choline supplementation mitigates premature foetal weight gain induced by an obesogenic diet, potentially linked to increased amniotic fluid leptin levels in rats","volume":"14","author":"Castillo","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e13064","DOI":"10.1111\/mcn.13064","article-title":"Maternal folate, one-carbon metabolism and pregnancy outcomes","volume":"17","author":"Furness","year":"2021","journal-title":"Matern. Child Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Xin, L., Wen, Y., Song, J., Chen, T., and Zhai, Q. (2023). Bone regeneration strategies based on organelle homeostasis of mesenchymal stem cells. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1151691"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lopomo, A., Ricciardi, R., Maestri, M., De Rosa, A., Melfi, F., Lucchi, M., Mussi, A., Copped\u00e8, F., and Migliore, L. (2016). Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122121"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12964-024-02025-7","article-title":"Role of sirtuins in obesity and osteoporosis: Molecular mechanisms and therapeutic targets","volume":"23","author":"Du","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ma, C., Sun, Y., Pi, C., Wang, H., Sun, H., Yu, X., Shi, Y., and He, X. (2020). Sirt3 Attenuates Oxidative Stress Damage and Rescues Cellular Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Superoxide Dismutase 2. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.599376"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1080\/15548627.2016.1210368","article-title":"SQSTM1\/p62 mediates crosstalk between autophagy and the UPS in DNA repair","volume":"12","author":"Hewitt","year":"2016","journal-title":"Autophagy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"793328","DOI":"10.3389\/fcell.2022.793328","article-title":"Selective Autophagy Receptor p62\/SQSTM1, a Pivotal Player in Stress and Aging","volume":"10","author":"Kumar","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1080\/15548627.2016.1214779","article-title":"CDK4-CDK6 inhibitors induce autophagy-mediated degradation of DNMT1 and facilitate the senescence antitumor response","volume":"12","author":"Bourdeau","year":"2016","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e0200324","DOI":"10.1128\/jvi.02003-24","article-title":"Autophagy-mediated TET2 degradation by ALV-J Env protein suppresses innate immune activation to promote viral replication","volume":"99","author":"Chen","year":"2025","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1073\/pnas.1121159109","article-title":"Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice","volume":"109","author":"Moresi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Smith, N., Shirazi, S., Cakouros, D., and Gronthos, S. (2023). Impact of Environmental and Epigenetic Changes on Mesenchymal Stem Cells during Aging. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076499"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"bio058534","DOI":"10.1242\/bio.058534","article-title":"DNMT1 is a negative regulator of osteogenesis","volume":"11","author":"Tao","year":"2022","journal-title":"Biol. Open"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.bcp.2019.03.023","article-title":"High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma","volume":"163","author":"Liu","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1038\/emboj.2009.405","article-title":"HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy","volume":"29","author":"Lee","year":"2010","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1186\/s13287-019-1441-4","article-title":"Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells","volume":"10","author":"Li","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1186\/s13018-025-06067-6","article-title":"Metformin facilitates osteogenic differentiation of bone marrow stromal cells through AMPK-dependent autophagy: An investigation into the healing of osteoporotic fractures in murine models","volume":"20","author":"Du","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41420-024-01850-6","article-title":"From the regulatory mechanism of TFEB to its therapeutic implications","volume":"10","author":"Chen","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e13126","DOI":"10.1111\/acel.13126","article-title":"C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis","volume":"19","author":"Wang","year":"2020","journal-title":"Aging Cell"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"La Spina, M., Contreras, P.S., Rissone, A., Meena, N.K., Jeong, E., and Martina, J.A. (2020). MiT\/TFE Family of Transcription Factors: An Evolutionary Perspective. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.609683"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101195","DOI":"10.1016\/j.arr.2020.101195","article-title":"TIP60 in aging and neurodegeneration","volume":"64","author":"Li","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1126\/science.1217032","article-title":"GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy","volume":"336","author":"Lin","year":"2012","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"AMPK: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4720","DOI":"10.1128\/MCB.06147-11","article-title":"SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities","volume":"31","author":"Peng","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41413-024-00351-7","article-title":"Rejuvenation of BMSCs senescence by pharmacological enhancement of TFEB-mediated autophagy alleviates aged-related bone loss and extends lifespan in middle aged mice","volume":"12","author":"Luo","year":"2024","journal-title":"Bone Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhu, C., Ding, H., Shi, L., Zhang, S., Tong, X., Huang, M., Liu, L., Guan, X., Zou, J., and Yuan, Y. (2023). Exercise improved bone health in aging mice: A role of SIRT1 in regulating autophagy and osteogenic differentiation of BMSCs. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1156637"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10735-020-09857-w","article-title":"Age-dependent role of SIRT6 in jawbone via regulating senescence and autophagy of bone marrow stromal cells","volume":"51","author":"Shen","year":"2020","journal-title":"J. Mol. Histol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1080\/15548627.2023.2186112","article-title":"The role of autophagy in bone metabolism and clinical significance","volume":"19","author":"Wang","year":"2023","journal-title":"Autophagy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1186\/s13287-022-03080-y","article-title":"Correction: Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss","volume":"13","author":"Zhang","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Lai, Z., Shu, Q., Song, Y., Tang, A., and Tian, J. (2024). Effect of DNA methylation on the osteogenic differentiation of mesenchymal stem cells: Concise review. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1429844"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4252\/wjsc.v16.i3.245","article-title":"How mesenchymal stem cells transform into adipocytes: Overview of the current understanding of adipogenic differentiation","volume":"16","author":"Liu","year":"2024","journal-title":"World J. Stem Cells"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20240968","DOI":"10.1515\/med-2024-0968","article-title":"Regulation of mesenchymal stem cell differentiation by autophagy","volume":"19","author":"Wei","year":"2024","journal-title":"Open Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.lfs.2011.06.007","article-title":"Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells","volume":"89","author":"Kanda","year":"2011","journal-title":"Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/s12276-023-00965-7","article-title":"Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway","volume":"55","author":"Kim","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e13622","DOI":"10.1111\/acel.13622","article-title":"Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation","volume":"21","author":"Zhong","year":"2022","journal-title":"Aging Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12935-025-03771-5","article-title":"Lysosomes: Guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment","volume":"25","author":"Bi","year":"2025","journal-title":"Cancer Cell Int."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41368-022-00204-1","article-title":"Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency","volume":"14","author":"Li","year":"2022","journal-title":"Int. J. Oral Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.1038\/s44318-024-00214-1","article-title":"Chromatin protein complexes involved in gene repression in lamina-associated domains","volume":"43","author":"Manzo","year":"2024","journal-title":"EMBO J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.devcel.2022.01.015","article-title":"Matrix remodeling controls a nuclear lamin A\/C-emerin network that directs Wnt-regulated stem cell fate","volume":"57","author":"Tang","year":"2022","journal-title":"Dev. Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"29752","DOI":"10.1021\/acsami.3c01481","article-title":"Histone Modification of Osteogenesis Related Genes Triggered by Substrate Topography Promotes Human Mesenchymal Stem Cell Differentiation","volume":"15","author":"Xu","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10046","DOI":"10.1038\/s41467-024-54338-3","article-title":"Disorganized chromatin hierarchy and stem cell aging in a male patient of atypical laminopathy-based progeria mandibuloacral dysplasia type A","volume":"15","author":"Jin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1172\/JCI77716","article-title":"MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation","volume":"125","author":"Li","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"118055","DOI":"10.1016\/j.lfs.2020.118055","article-title":"Inhibition of miR-34a reduces cellular senescence in human adipose tissue-derived mesenchymal stem cells through the activation of SIRT1","volume":"257","author":"Mokhberian","year":"2020","journal-title":"Life Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"13421","DOI":"10.1073\/pnas.0801613105","article-title":"miR-34a repression of SIRT1 regulates apoptosis","volume":"105","author":"Yamakuchi","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1111\/jcmm.16139","article-title":"The miRNA-15b\/USP7\/KDM6B axis engages in the initiation of osteoporosis by modulating osteoblast differentiation and autophagy","volume":"25","author":"Lu","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41418-021-00858-0","article-title":"LncRNA NEAT1 controls the lineage fates of BMSCs during skeletal aging by impairing mitochondrial function and pluripotency maintenance","volume":"29","author":"Zhang","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/s42003-023-05493-8","article-title":"LncRNA SNHG14 activates autophagy via regulating miR-493-5p\/Mef2c axis to alleviate osteoporosis progression","volume":"6","author":"Xue","year":"2023","journal-title":"Commun. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"28897","DOI":"10.1038\/srep28897","article-title":"Long Non-coding RNA H19 Inhibits Adipocyte Differentiation of Bone Marrow Mesenchymal Stem Cells through Epigenetic Modulation of Histone Deacetylases","volume":"6","author":"Huang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Sigmarsdottir, T.B., McGarrity, S., de Lomana, A.L.G., Kotronoulas, A., Sigurdsson, S., Yurkovich, J.T., Rolfsson, O., and Sigurjonsson, O.E. (2021). Metabolic and Transcriptional Changes across Osteogenic Differentiation of Mesenchymal Stromal Cells. Bioengineeing, 8.","DOI":"10.3390\/bioengineering8120208"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ye, J., Xiao, J., Wang, J., Ma, Y., Zhang, Y., Zhang, Q., Zhang, Z., and Yin, H. (2021). The Interaction Between Intracellular Energy Metabolism and Signaling Pathways During Osteogenesis. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.807487"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"31582","DOI":"10.1074\/jbc.M506736200","article-title":"Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation","volume":"280","author":"Onodera","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.4161\/auto.36182","article-title":"Autophagy in osteoblasts is involved in mineralization and bone homeostasis","volume":"10","author":"Nollet","year":"2014","journal-title":"Autophagy"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41419-022-04906-6","article-title":"Mitochondrial autophagy: Molecular mechanisms and implications for cardiovascular disease","volume":"13","author":"Li","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"C1637","DOI":"10.1152\/ajpcell.00951.2024","article-title":"Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease","volume":"328","author":"Kuchay","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wang, G., Luo, J., Qiao, Y., Zhang, D., Liu, Y., Zhang, W., Liu, X., and Jiang, X. (2022). AMPK\/mTOR Pathway Is Involved in Autophagy Induced by Magnesium-Incorporated TiO2 Surface to Promote BMSC Osteogenic Differentiation. J. Funct. Biomater., 13.","DOI":"10.3390\/jfb13040221"},{"key":"ref_81","first-page":"2535","article-title":"AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction","volume":"41","author":"Li","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1186\/s13287-024-04014-6","article-title":"Improvement of osteogenic differentiation potential of placenta-derived mesenchymal stem cells by metformin via AMPK pathway activation","volume":"15","author":"Manochantr","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4056","DOI":"10.1038\/s41467-020-17882-2","article-title":"Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites","volume":"11","author":"Bosc","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/s41392-023-01503-7","article-title":"The mitophagy pathway and its implications in human diseases","volume":"8","author":"Wang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"L1324","DOI":"10.1152\/ajplung.00326.2001","article-title":"Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes","volume":"282","author":"Kulisz","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41421-024-00689-6","article-title":"Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis","volume":"10","author":"Zhu","year":"2024","journal-title":"Cell Discov."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Komori, T. (2024). Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251810102"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e10496","DOI":"10.1002\/jbm4.10496","article-title":"Single-Cell RNA-Sequencing Reveals the Breadth of Osteoblast Heterogeneity","volume":"5","author":"Yoshioka","year":"2021","journal-title":"JBMR Plus"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"20629","DOI":"10.18632\/aging.203452","article-title":"A systematic dissection of human primary osteoblasts in vivo at single-cell resolution","volume":"13","author":"Gong","year":"2021","journal-title":"Aging"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"117442","DOI":"10.1016\/j.bone.2025.117442","article-title":"Unraveling the dynamics of osteoblast differentiation in MC3T3-E1 cells: Transcriptomic insights into matrix mineralization and cell proliferation","volume":"194","author":"Yoon","year":"2025","journal-title":"Bone"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"116643","DOI":"10.1016\/j.bone.2022.116643","article-title":"Hyperlipidemia impacts osteogenesis via lipophagy","volume":"167","author":"Ji","year":"2023","journal-title":"Bone"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"5262","DOI":"10.1080\/21655979.2022.2037881","article-title":"Effects of runt-related transcription factor 2 (RUNX2) on the autophagy of rapamycin-treated osteoblasts","volume":"13","author":"Ren","year":"2022","journal-title":"Bioengineered"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3892\/etm.2024.12617","article-title":"The role of autophagy\/lipophagy in the response of osteoblastic cells to hyperlipidemia (Review)","volume":"28","author":"He","year":"2024","journal-title":"Exp. Ther. Med."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Gu, Y., Wu, Z., Xie, H., Fang, T., Wang, Q., and Gu, Y. (2024). Regulatory signaling pathways of osteoblast autophagy in periprosthetic osteolysis. Front. Cell Death, 3.","DOI":"10.3389\/fceld.2024.1337724"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"111598","DOI":"10.1016\/j.cellsig.2025.111598","article-title":"Mechanisms of Ferroptosis in bone disease: A new target for osteoporosis treatment","volume":"127","author":"Wang","year":"2025","journal-title":"Cell Signal"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"123637","DOI":"10.1016\/j.biomaterials.2025.123637","article-title":"An activatable polymeric nano-spy for reversing the progression of diabetic osteoporosis","volume":"325","author":"Li","year":"2026","journal-title":"Biomaterials"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3892\/ijmm.2021.4909","article-title":"Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro","volume":"47","author":"Wang","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Rivas, M., Gupta, G., Costanzo, L., Ahmed, H., Wyman, A.E., and Geraghty, P. (2022). Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease. Medicina, 58.","DOI":"10.3390\/medicina58060817"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"166412","DOI":"10.1016\/j.bbadis.2022.166412","article-title":"The role of autophagy in the metabolism and differentiation of stem cells","volume":"1868","author":"Adelipour","year":"2022","journal-title":"Biochim. Et Biophys. Acta Mol. Basis Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"684736","DOI":"10.1155\/2013\/684736","article-title":"Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation","volume":"2013","author":"James","year":"2013","journal-title":"Scientifica"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/bjh.13299","article-title":"RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype","volume":"169","author":"Maddipoti","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/s13287-019-1338-2","article-title":"Decitabine assists umbilical cord-derived mesenchymal stem cells in improving glucose homeostasis by modulating macrophage polarization in type 2 diabetic mice","volume":"10","author":"Gao","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e2305336","DOI":"10.1002\/smll.202305336","article-title":"Bone-Targeted Nanoparticle Drug Delivery System-Mediated Macrophage Modulation for Enhanced Fracture Healing","volume":"20","author":"Xiao","year":"2024","journal-title":"Small"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13072-018-0247-4","article-title":"Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination","volume":"12","author":"Cakouros","year":"2019","journal-title":"Epigenet. Chrom."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Kim, K.T., Lee, Y.S., and Han, I. (2020). The Role of Epigenomics in Osteoporosis and Osteoporotic Vertebral Fracture. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249455"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"5017","DOI":"10.1007\/s12035-016-0035-8","article-title":"Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways","volume":"54","author":"Geoffroy","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e12709","DOI":"10.1111\/acel.12709","article-title":"Autophagy controls mesenchymal stem cell properties and senescence during bone aging","volume":"17","author":"Ma","year":"2018","journal-title":"Aging Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13018-023-03616-9","article-title":"Osteogenic effects of rapamycin on bone marrow mesenchymal stem cells via inducing autophagy","volume":"18","author":"Xing","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41419-023-06154-8","article-title":"Autophagy: Regulator of cell death","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on mechanisms of action and repurposing potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e191688","DOI":"10.1172\/jci.insight.191688","article-title":"Elevation of master autophagy regulator Tfeb in osteoblast lineage cells increases bone mass and strength","volume":"10","author":"James","year":"2025","journal-title":"JCI Insight"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1111\/acer.14695","article-title":"Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol-impaired TFEB and liver injury in mice","volume":"45","author":"Chao","year":"2021","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1038\/s12276-023-01055-4","article-title":"Pancreatic \u03b2-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release","volume":"55","author":"Oh","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1080\/13510002.2019.1658376","article-title":"Resveratrol improves osteogenic differentiation of senescent bone mesenchymal stem cells through inhibiting endogenous reactive oxygen species production via AMPK activation","volume":"24","author":"Zhou","year":"2019","journal-title":"Redox Rep."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2485666","DOI":"10.1080\/13510002.2025.2485666","article-title":"Spermidine prevents iron overload-induced impaired bone mass by activating SIRT1\/SOD2 signaling in senile rat model","volume":"30","author":"Du","year":"2025","journal-title":"Redox Rep."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Wang, M., and Yu, L. (2025). Emerging evidence of Urolithin A in sports nutrition: Bridging preclinical findings to athletic applications. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1585922"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3892\/ijmm.2024.5445","article-title":"Quercetin ameliorates senescence and promotes osteogenesis of BMSCs by suppressing the repetitive element-triggered RNA sensing pathway","volume":"55","author":"Sun","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Yun, H.M., Kim, B., Park, J.E., and Park, K.R. (2022). Trifloroside Induces Bioactive Effects on Differentiation, Adhesion, Migration, and Mineralization in Pre-Osteoblast MC3T3E-1 Cells. Cells, 11.","DOI":"10.3390\/cells11233887"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.2147\/IJN.S444347","article-title":"Bone Targeting Nanoparticles for the Treatment of Osteoporosis","volume":"19","author":"Wen","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Lin, Y., Xu, Y., Zhou, S., Liu, J., Zhang, M., Zhang, B., and Chen, H. (2025). Updated Advances on Drugs and Bone-Targeting Nanoparticles for Osteoporosis Therapy: Carrier Materials, Modification, Function Mechanism, and Applications\u2014A Systematic Review. Pharmaceuticals, 18.","DOI":"10.3390\/ph18121809"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41413-024-00356-2","article-title":"Bone targeted nano-drug and nano-delivery","volume":"12","author":"Wu","year":"2024","journal-title":"Bone Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40824-023-00413-7","article-title":"Emerging nano-scale delivery systems for the treatment of osteoporosis","volume":"27","author":"Dayanandan","year":"2023","journal-title":"Biomater. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"7983","DOI":"10.2147\/IJN.S462514","article-title":"Alendronate Functionalized Bone-Targeting Pomolic Acid Liposomes Restore Bone Homeostasis for Osteoporosis Treatment","volume":"19","author":"Xia","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"16557","DOI":"10.1021\/acs.jafc.5c02681","article-title":"Rosmarinic Acid Ameliorates Type 2 Diabetic Osteoporosis by Reducing NLRP3 Expression and Alleviating Osteoblast Pyroptosis via the FOXO1\/TXNIP Signaling Pathway","volume":"73","author":"Feng","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Zhang, L., Zheng, Y.L., Wang, R., Wang, X.Q., and Zhang, H. (2022). Exercise for osteoporosis: A literature review of pathology and mechanism. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1005665"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.14336\/AD.2024.0318","article-title":"Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population","volume":"16","author":"Wang","year":"2024","journal-title":"Aging Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e10386","DOI":"10.1002\/smll.202510386","article-title":"Targeted Delivery of Exosomal Bmp2 mRNA via a Bioadhesive Interface Synergistically Enhances Titanium Implant Osseointegration","volume":"21","author":"Yang","year":"2025","journal-title":"Small"},{"key":"ref_129","first-page":"207","article-title":"A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis","volume":"10","author":"Cui","year":"2022","journal-title":"Bioact. Mater."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/218\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:15:09Z","timestamp":1769490909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/3\/218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,24]]},"references-count":129,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["biology15030218"],"URL":"https:\/\/doi.org\/10.3390\/biology15030218","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,24]]}}}