{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:57:55Z","timestamp":1793419075345,"version":"4.5.0"},"reference-count":73,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shandong Province Technology Innovation Guidance Program","award":["YDZX2024122"],"award-info":[{"award-number":["YDZX2024122"]}]},{"name":"Jinan \u201c20 New Universities\u201d Funding Project","award":["202228121"],"award-info":[{"award-number":["202228121"]}]},{"name":"Jinan \u201c20 New Universities\u201d Funding Project","award":["202333006"],"award-info":[{"award-number":["202333006"]}]},{"name":"Taishan Scholars Project","award":["tstp 20231239"],"award-info":[{"award-number":["tstp 20231239"]}]},{"name":"Chinese Medicine State Administration","award":["GDY-KJS-2023-027"],"award-info":[{"award-number":["GDY-KJS-2023-027"]}]},{"name":"Shandong Traditional Chinese Medicine Science and Technology Project","award":["M-2023291T"],"award-info":[{"award-number":["M-2023291T"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Di(2-ethylhexyl) phthalate (DEHP), a widely employed exogenous plasticizer, has become pervasive in the environment and living organisms due to its extensive use in food packaging, medical devices, and daily consumer products, and is established as a typical endocrine-disrupting chemical. Growing evidence indicates a strong association between DEHP exposure and the incidence of chronic bone disorders, including osteoporosis (OP), osteoarthritis (OA), and osteonecrosis of the femoral head (ONFH). However, the molecular mechanisms underlying its pathogenic effects across these diseases remain poorly defined. In this study, we applied an environmental network toxicology approach to integrate predicted protein targets of DEHP with known disease-associated targets of the three bone disorders using multiple databases. Through Venn analysis, protein\u2013protein interaction (PPI) network construction, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we identified core targets and key signaling pathways. Molecular docking and molecular dynamics (MD) simulations were further employed to validate the binding modes and stability between DEHP and the core targets, thereby elucidating common and distinct mechanisms of DEHP across these bone diseases. A total of 109 overlapping targets of DEHP and the three bone diseases were identified, among which 7 core targets\u2014AKT1, SRC, ESR1, CASP3, MMP9, BCL2, and BCL2L1\u2014were common to all three disorders. These are implicated in critical biological processes such as apoptosis regulation, inflammation, extracellular matrix degradation, and estrogen signaling. KEGG enrichment analysis revealed significant involvement of the PI3K-Akt, MAPK, Ras, TNF, and estrogen signaling pathways across all three diseases. Molecular docking and MD simulations confirmed stable binding of DEHP to key targets including AKT1, ESR1, and MMP9, supporting its potential to disrupt bone metabolic homeostasis via multi-target and multi-pathway mechanisms. Further analysis indicated that DEHP exerts both shared and disease-specific effects: it disrupts osteoblast\/osteoclast balance in OP, amplifies inflammatory responses and matrix degradation in OA, and contributes to impaired angiogenesis and osteocyte necrosis in ONFH. This study systematically reveals how DEHP disrupts bone homeostasis through a multi-target and multi-pathway network, constructing a cross-disease osteotoxicity framework. It is the first to delineate the common and distinct molecular mechanisms of DEHP in OP, OA, and ONFH. Although these insights are derived from computational models and require further experimental validation, they provide a novel theoretical basis for combined intervention strategies targeting multiple bone diseases and for environmental health risk assessment.<\/jats:p>","DOI":"10.3390\/ijms262210895","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:51:08Z","timestamp":1762782668000},"page":"10895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Network Toxicology and Molecular Docking Reveal the Toxicological Mechanisms of DEHP in Bone Diseases"],"prefix":"10.3390","volume":"26","author":[{"given":"Zhonghao","family":"Fan","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-6648","authenticated-orcid":false,"given":"Haitao","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1268-4625","authenticated-orcid":false,"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiefeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine Pharmacology (Pharmacological Experimentation Center), Shandong Academy of Chinese Medicine, Jinan 250014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zeng, F., Zhang, L., Deng, F., and Lou, S. (2023). Early-Life Exposure to Di (2-Ethyl-Hexyl) Phthalate: Role in Children with Endocrine Disorders. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1115229"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44952","DOI":"10.1007\/s11356-023-25405-x","article-title":"Non-Persistent Chemicals in Polymer and Non-Polymer Products Can Cause Persistent Environmental Contamination: Evidence with DEHP in Europe","volume":"30","author":"Chapon","year":"2023","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11899","DOI":"10.1021\/acs.langmuir.0c01964","article-title":"Stabilization of Lipid Membranes through Partitioning of the Blood Bag Plasticizer Di-2-Ethylhexyl Phthalate (DEHP)","volume":"36","author":"Bider","year":"2020","journal-title":"Langmuir"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2174\/1570159X19666210713122517","article-title":"Effects of Di-2-Ethylhexyl Phthalate on Central Nervous System Functions: A Narrative Review","volume":"20","author":"Safarpour","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11006","DOI":"10.1021\/acs.est.2c03497","article-title":"Coupled Dynamic Material Flow, Multimedia Environmental Model, and Ecological Risk Analysis for Chemical Management: A Di(2-Ethylhexhyl) Phthalate Case in China","volume":"56","author":"Cui","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Carli, F., Tait, S., Busani, L., Ciociaro, D., Della Latta, V., Pala, A.P., Deodati, A., Raffaelli, A., Pratesi, F., and Conte, R. (2022). Exposure to Endocrine Disruptors (Di(2-Ethylhexyl)Phthalate (DEHP) and Bisphenol A (BPA)) in Women from Different Residing Areas in Italy: Data from the LIFE PERSUADED Project. Int. J. Mol. Sci., 23.","DOI":"10.1101\/2022.05.31.22275004"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Xu, L., Yan, J., Yin, T., Pan, Y., Chen, M., Wang, X., Wu, L., and Ding, H. (2025). Di (2-Ethylhexyl) Phthalate Decrease Pregnancy Rate via Disrupting the Microbe-Gut-Hypothalamic-Pituitary-Ovarian Axis in Mice. npj Biofilms Microbiomes, 11.","DOI":"10.1038\/s41522-025-00742-6"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Z., and Wang, Y. (2025). Mechanism Exploration of Di(2-Ethylhexyl) Phthalate (DEHP)-Induced Breast Cancer via Network Toxicology and Molecular Docking Analysis. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-13201-1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"369","DOI":"10.21037\/tau-23-503","article-title":"Prenatal DEHP Exposure Induces Lifelong Testicular Toxicity by Continuously Interfering with Steroidogenic Gene Expression","volume":"13","author":"Xie","year":"2024","journal-title":"Transl. Androl. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17005","DOI":"10.1289\/EHP9373","article-title":"Role of Hepatocyte- and Macrophage-Specific PPAR\u03b3 in Hepatotoxicity Induced by Diethylhexyl Phthalate in Mice","volume":"130","author":"Xu","year":"2022","journal-title":"Environ. Health Perspect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/rcm.8258","article-title":"Mono(2-Ethylhexyl) Phthalate (MEHP) and Mono(2-Ethyl-5-Oxohexyl) Phthalate (MEOHP) but Not Di(2-Ethylhexyl) Phthalate (DEHP) Bind Productively to the Peroxisome Proliferator-Activated Receptor \u03b3","volume":"33","author":"Kratochvil","year":"2019","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"156815","DOI":"10.1016\/j.scitotenv.2022.156815","article-title":"Di-(2-Ethylhexyl) Phthalate Increases Plasma Glucose and Induces Lipid Metabolic Disorders via FoxO1 in Adult Mice","volume":"842","author":"Wei","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1093\/toxres\/tfad022","article-title":"Di(2-Ethylhexyl) Phthalate Mediates Oxidative Stress and Activates p38MAPK\/NF-kB to Exacerbate Diabetes-Induced Kidney Injury In Vitro and In Vivo Models","volume":"12","author":"Ding","year":"2023","journal-title":"Toxicol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41392-024-01757-9","article-title":"NF-\u03baB in Biology and Targeted Therapy: New Insights and Translational Implications","volume":"9","author":"Guo","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169918","DOI":"10.1016\/j.scitotenv.2024.169918","article-title":"Chronic Di(2-Ethylhexyl) Phthalate Exposure at Environmental-Relevant Doses Induces Osteoporosis by Disturbing the Differentiation of Bone Marrow Mesenchymal Stem Cells","volume":"914","author":"Zhang","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12940-022-00920-5","article-title":"Phthalates and Bone Mineral Density: A Systematic Review","volume":"21","author":"Heilmann","year":"2022","journal-title":"Environ. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1111\/1756-185X.14386","article-title":"Di-(2-Ethylhexyl) Phthalate Exposure Links to Inflammation and Low Bone Mass in Premenopausal and Postmenopausal Females: Evidence from Ovariectomized Mice and Humans","volume":"25","author":"Lai","year":"2022","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"704","DOI":"10.2174\/1871530321666210118163538","article-title":"Bone Disruption and Environmental Pollutants","volume":"22","author":"Giannattasio","year":"2022","journal-title":"Endocr. Metab. Immune Disord.-Drug Targets"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhang, Y., and Chen, Q. (2023). Novel Insights into Osteocyte and Inter-Organ\/Tissue Crosstalk. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1308408"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/s41467-017-02541-w","article-title":"Direct Cell-Cell Contact between Mature Osteoblasts and Osteoclasts Dynamically Controls Their Functions In Vivo","volume":"9","author":"Furuya","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hsu, S.-H., Chen, L.-R., and Chen, K.-H. (2024). Primary Osteoporosis Induced by Androgen and Estrogen Deficiency: The Molecular and Cellular Perspective on Pathophysiological Mechanisms and Treatments. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212139"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16009","DOI":"10.1038\/boneres.2016.9","article-title":"TGF-\u03b2 and BMP Signaling in Osteoblast, Skeletal Development, and Bone Formation, Homeostasis and Disease","volume":"4","author":"Wu","year":"2016","journal-title":"Bone Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lecka-Czernik, B., Rosen, C.J., and Napoli, N. (2025). The Role of Bone in Whole-Body Energy Metabolism. Nat. Rev. Endocrinol.","DOI":"10.1038\/s41574-025-01162-4"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112614","DOI":"10.1016\/j.exger.2024.112614","article-title":"The Interplay between Osteoarthritis and Osteoporosis: Mechanisms, Implications, and Treatment Considerations\u2013A Narrative Review","volume":"197","author":"Huang","year":"2024","journal-title":"Exp. Gerontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0140-6736(24)02322-5","article-title":"Osteoarthritis","volume":"405","author":"Kloppenburg","year":"2025","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1302\/2046-3758.111.BJR-2021-0467.R1","article-title":"Osteoimmunology and Osteonecrosis of the Femoral Head","volume":"11","author":"Ma","year":"2022","journal-title":"Bone Joint Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/s12276-025-01481-6","article-title":"Progressing Future Osteoarthritis Treatment toward Precision Medicine: Integrating Regenerative Medicine, Gene Therapy and Circadian Biology","volume":"57","author":"Kim","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Khan, N.M., Haseeb, A., Ansari, M.Y., and Haqqi, T.M. (2017). A Wogonin-Rich-Fraction of Scutellaria baicalensis Root Extract Exerts Chondroprotective Effects by Suppressing IL-1\u03b2-Induced Activation of AP-1 in Human OA Chondrocytes. Sci. Rep., 7.","DOI":"10.1038\/srep43789"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e177","DOI":"10.3346\/jkms.2021.36.e177","article-title":"Osteonecrosis of the Femoral Head: An Updated Review of ARCO on Pathogenesis, Staging and Treatment","volume":"36","author":"Hines","year":"2021","journal-title":"J. Korean Med. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, J., Cao, J., Liu, Y., and Zhao, H. (2024). Advances in the Pathogenesis of Steroid-Associated Osteonecrosis of the Femoral Head. Biomolecules, 14.","DOI":"10.3390\/biom14060667"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2416070","DOI":"10.1080\/07853890.2024.2416070","article-title":"Pathological Mechanisms and Related Markers of Steroid-Induced Osteonecrosis of the Femoral Head","volume":"56","author":"Li","year":"2024","journal-title":"Ann. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhivodernikov, I.V., Kirichenko, T.V., Markina, Y.V., Postnov, A.Y., and Markin, A.M. (2023). Molecular and Cellular Mechanisms of Osteoporosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115772"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.mcna.2022.10.013","article-title":"Osteoporosis","volume":"107","author":"Gopinath","year":"2023","journal-title":"Med. Clin. N. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"114377","DOI":"10.1016\/j.intimp.2025.114377","article-title":"DPHB Inhibits Osteoclastogenesis by Suppressing NF-\u03baB and MAPK Signaling and Alleviates Inflammatory Bone Destruction","volume":"152","author":"Liu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104391","DOI":"10.1016\/j.etap.2024.104391","article-title":"Impact of DEHP Exposure on Female Reproductive Health: Insights into Uterine Effects","volume":"107","author":"Kawa","year":"2024","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Valls-Margarit, J., Pi\u00f1ero, J., F\u00fczi, B., Cerisier, N., Taboureau, O., and Furlong, L.I. (2023). Assessing Network-Based Methods in the Context of System Toxicology. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1225697"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119480","DOI":"10.1016\/j.jep.2025.119480","article-title":"Application and Development Trends of Network Toxicology in the Safety Assessment of Traditional Chinese Medicine","volume":"343","author":"Li","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shah, A.B., Baiseitova, A., Amzeyeva, U., Shang, X., and Jenis, J. (2025). \u03b1-Glucosidase Inhibition-Guided Network Pharmacology and Molecular Docking Reveal the Antidiabetic Potential of Cichorium intybus as a Functional Food. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199497"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e41632","DOI":"10.1016\/j.heliyon.2025.e41632","article-title":"Exosomal Non-Coding RNAs in the Regulation of Bone Metabolism Homeostasis: Molecular Mechanism and Therapeutic Potential","volume":"11","author":"Huang","year":"2025","journal-title":"Heliyon"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Gy\u0151ri, D.S. (2024). Research on Bone Cells in Health and Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168758"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"169","DOI":"10.11005\/jbm.2019.26.3.169","article-title":"Effects of Di(2-Ethylhexyl)Phthalate on Bone Metabolism in Ovariectomized Mice","volume":"26","author":"Choi","year":"2019","journal-title":"J. Bone Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Liu, C., Zhang, J., Ye, Z., Luo, J., Peng, B., and Wang, Z. (2025). Research on the Role and Mechanism of the PI3K\/Akt\/mTOR Signalling Pathway in Osteoporosis. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1541714"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Matsubara, T., Yasuda, K., Mizuta, K., Kawaue, H., and Kokabu, S. (2022). Tyrosine Kinase Src Is a Regulatory Factor of Bone Homeostasis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105508"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pelusi, L., Mandatori, D., Di Pietrantonio, N., Del Pizzo, F., Di Tomo, P., Di Pietro, N., Buda, R., Genovese, S., Epifano, F., and Pandolfi, A. (2022). Estrogen Receptor 1 (ESR1) and the Wnt\/\u03b2-Catenin Pathway Mediate the Effect of the Coumarin Derivative Umbelliferon on Bone Mineralization. Nutrients, 14.","DOI":"10.3390\/nu14153209"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e35461","DOI":"10.1097\/MD.0000000000035461","article-title":"Association between the ESR1 and ESR2 Polymorphisms and Osteoporosis Risk: An Updated Meta-Analysis","volume":"102","author":"Bai","year":"2023","journal-title":"Medicine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3892\/mmr.2024.13268","article-title":"Estrogen Receptor Signaling and Targets: Bones, Breasts and Brain (Review)","volume":"30","author":"Toumba","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s10020-022-00449-w","article-title":"Phosphorylation of BCL2 at the Ser70 Site Mediates RANKL-Induced Osteoclast Precursor Autophagy and Osteoclastogenesis","volume":"28","author":"Ke","year":"2022","journal-title":"Mol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41392-025-02176-0","article-title":"The BCL2 Family: From Apoptosis Mechanisms to New Advances in Targeted Therapy","volume":"10","author":"Vogler","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41580-023-00629-4","article-title":"Mechanisms of BCL-2 Family Proteins in Mitochondrial Apoptosis","volume":"24","author":"Czabotar","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41420-024-01826-6","article-title":"Dependence of Human Cell Survival and Proliferation on the CASP3 Prodomain","volume":"10","author":"Eskandari","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_51","first-page":"7249","article-title":"MiR-378 Overexpression Attenuates High Glucose-Suppressed Osteogenic Differentiation through Targeting CASP3 and Activating PI3K\/Akt Signaling Pathway","volume":"7","author":"You","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1172\/JCI20427","article-title":"A Crucial Role of Caspase-3 in Osteogenic Differentiation of Bone Marrow Stromal Stem Cells","volume":"114","author":"Miura","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Iantomasi, T., Romagnoli, C., Palmini, G., Donati, S., Falsetti, I., Miglietta, F., Aurilia, C., Marini, F., Giusti, F., and Brandi, M.L. (2023). Oxidative Stress and Inflammation in Osteoporosis: Molecular Mechanisms Involved and the Relationship with microRNAs. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043772"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/s41419-020-03059-8","article-title":"Osteocyte Apoptosis: The Roles and Key Molecular Mechanisms in Resorption-Related Bone Diseases","volume":"11","author":"Ru","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Chen, Y., Zou, J., Niimi, M., Qiu, X., Zhang, S., Yang, H., Zhu, M., and Fan, J. (2025). Matrix Metalloproteinase-9 Enhances Osteoclastogenesis: Insights from Transgenic Rabbit Bone Marrow Models and In Vitro Studies. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073194"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"102862","DOI":"10.1016\/j.tice.2025.102862","article-title":"MMP-9 Expression in Bone Cells in the Developing Femur","volume":"95","author":"Mustafa","year":"2025","journal-title":"Tissue Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1039\/D3GC03428C","article-title":"Global Environmental and Toxicological Data of Emerging Plasticizers: Current Knowledge, Regrettable Substitution Dilemma, Green Solution and Future Perspectives","volume":"26","author":"Qadeer","year":"2024","journal-title":"Green Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An Updated Comprehensive Online ADMET Prediction Platform Enhanced with Broader Coverage, Improved Performance, API Functionality and Decision Support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A Webserver for the Prediction of Toxicity of Chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated Data and New Features for Efficient Prediction of Protein Targets of Small Molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nbt1284","article-title":"Relating Protein Pharmacology by Ligand Chemistry","volume":"25","author":"Keiser","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"D1180","DOI":"10.1093\/nar\/gkad1004","article-title":"The ChEMBL Database in 2023: A Drug Discovery Platform Spanning Multiple Bioactivity Data Types and Time Periods","volume":"52","author":"Zdrazil","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"W609","DOI":"10.1093\/nar\/gkq300","article-title":"PharmMapper Server: A Web Server for Potential Drug Target Identification Using Pharmacophore Mapping Approach","volume":"38","author":"Liu","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_64","unstructured":"UniProt Consortium (2025). UniProt: The Universal Protein Knowledgebase in 2025. Nucleic Acids Res., 53, D609\u2013D617."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING Database in 2023: Protein-Protein Association Networks and Functional Enrichment Analyses for Any Sequenced Genome of Interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Bader, G.D., and Hogue, C.W.V. (2003). An Automated Method for Finding Molecular Complexes in Large Protein Interaction Networks. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-2"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Chin, C.-H., Chen, S.-H., Wu, H.-H., Ho, C.-W., Ko, M.-T., and Lin, C.-Y. (2014). cytoHubba: Identifying Hub Objects and Sub-Networks from Complex Interactome. BMC Syst. Biol., 8.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A Web Server for Functional Enrichment Analysis and Functional Annotation of Gene Lists (2021 Update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate Structure Prediction of Biomolecular Interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"W463","DOI":"10.1093\/nar\/gkaf361","article-title":"PLIP 2025: Introducing Protein-Protein Interactions to the Protein-Ligand Interaction Profiler","volume":"53","author":"Schake","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"11603","DOI":"10.1021\/jacs.9b04383","article-title":"Opposing Temperature Dependence of the Stretching Response of Single PEG and PNiPAM Polymers","volume":"141","author":"Kolberg","year":"2019","journal-title":"J. Am. Chem. Soc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10895\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T09:58:52Z","timestamp":1763459932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":73,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210895"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210895","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]}}}