{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:39:31Z","timestamp":1792431571558,"version":"4.5.0"},"reference-count":50,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Experimental Gerontology"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.exger.2026.113316","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:06:40Z","timestamp":1789024000000},"page":"113316","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Integrative network toxicology, molecular docking, and in vitro experiments identify SLC6A2 as a novel candidate target in nicotine-induced osteoporosis"],"prefix":"10.1016","volume":"224","author":[{"given":"Bo","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuwang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.exger.2026.113316_bb0005","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1619835","article-title":"Impact of smoking on the complement system: a narrative review","volume":"16","author":"Alarabi","year":"2025","journal-title":"Front. Immunol."},{"key":"10.1016\/j.exger.2026.113316_bb0010","article-title":"Exposure to 16 Hz pulsed electromagnetic fields protect the structural integrity of primary cilia and associated TGF-\u03b2 signaling in osteoprogenitor cells harmed by cigarette smoke","volume":"22","author":"Chen","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.exger.2026.113316_bb0015","article-title":"From neuromodulation to bone homeostasis: therapeutic targets of nerve growth factor in skeletal diseases","volume":"16","author":"Chen","year":"2025","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.exger.2026.113316_bb0020","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s00586-024-08553-7","article-title":"Serum IL-6 and TGF-\u03b21 concentrations as diagnostic biomarkers in elderly male patients with osteoporosis","volume":"34","author":"Chen","year":"2025","journal-title":"Eur. Spine J."},{"key":"10.1016\/j.exger.2026.113316_bb0025","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.pcad.2025.07.007","article-title":"How to facilitate smoking cessation","volume":"92","author":"Colivicchi","year":"2025","journal-title":"Prog. Cardiovasc. Dis."},{"key":"10.1016\/j.exger.2026.113316_bb0030","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1016\/S0140-6736(02)08657-9","article-title":"Epidemiology and outcomes of osteoporotic fractures","volume":"359","author":"Cummings","year":"2002","journal-title":"Lancet"},{"key":"10.1016\/j.exger.2026.113316_bb0035","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.biopha.2018.11.103","article-title":"Dexamethasone induces osteoblast apoptosis through ROS-PI3K\/AKT\/GSK3\u03b2 signaling pathway","volume":"110","author":"Deng","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"10.1016\/j.exger.2026.113316_bb0040","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23052701","article-title":"Age related osteoporosis: targeting cellular senescence","volume":"23","author":"F\u00f6ger-Samwald","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.exger.2026.113316_bb0045","doi-asserted-by":"crossref","DOI":"10.1111\/jcmm.70759","article-title":"Unravelling osteoporosis: key genes and potential therapies","volume":"29","author":"Fu","year":"2025","journal-title":"J. Cell. Mol. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0050","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41392-025-02384-8","article-title":"GPR15 differentially regulates the effects of cigarette smoke exposure on Crohn\u2019s disease and ulcerative colitis","volume":"10","author":"Gao","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"10.1016\/j.exger.2026.113316_bb0055","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/S2213-2600(17)30293-X","article-title":"Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015","volume":"5","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0060","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2024.1450328","article-title":"The role of calcium channels in osteoporosis and their therapeutic potential","volume":"15","author":"Hao","year":"2024","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"10.1016\/j.exger.2026.113316_bb0065","doi-asserted-by":"crossref","DOI":"10.1016\/j.ecoenv.2025.118132","article-title":"Exploring the link between Di-2-ethylhexyl phthalate (DEHP) exposure and muscle mass: a systematic investigation utilizing NHANES data analysis, network toxicology and molecular docking approaches","volume":"295","author":"Hao","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"10.1016\/j.exger.2026.113316_bb0070","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00223-010-9426-4","article-title":"Effects of nicotine administration and nicotine cessation on bone histomorphometry and bone biomarkers in Sprague-Dawley male rats","volume":"88","author":"Hapidin","year":"2011","journal-title":"Calcif. Tissue Int."},{"key":"10.1016\/j.exger.2026.113316_bb0075","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1679987","article-title":"Deciphering oligomeric proanthocyanidins\u2019 dual osteoprotective mechanisms at single-cell resolution: NR4A1-mediated PTGS2 suppression and \u03b2-catenin-Runx2 activation","volume":"16","author":"Huang","year":"2025","journal-title":"Front. Immunol."},{"key":"10.1016\/j.exger.2026.113316_bb0080","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1001\/jama.292.17.2105","article-title":"Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes","volume":"292","author":"Ioannidis","year":"2004","journal-title":"JAMA"},{"key":"10.1016\/j.exger.2026.113316_bb0085","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22147752","article-title":"Evaluation of MC3T3-E1 cell osteogenesis in different cell culture media","volume":"22","author":"Izumiya","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.exger.2026.113316_bb0090","doi-asserted-by":"crossref","DOI":"10.1016\/j.redox.2023.102922","article-title":"Tobacco toxins induce osteoporosis through ferroptosis","volume":"67","author":"Jing","year":"2023","journal-title":"Redox Biol."},{"key":"10.1016\/j.exger.2026.113316_bb0095","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s00774-012-0382-0","article-title":"Peroxisome proliferator-activated receptor delta agonist attenuates nicotine suppression effect on human mesenchymal stem cell-derived osteogenesis and involves increased expression of heme oxygenase-1","volume":"31","author":"Kim","year":"2013","journal-title":"J. Bone Miner. Metab."},{"key":"10.1016\/j.exger.2026.113316_bb0100","doi-asserted-by":"crossref","DOI":"10.3390\/cells10051199","article-title":"Modulation of endocannabinoid tone in osteoblastic differentiation of MC3T3-E1 cells and in mouse bone tissue over time","volume":"10","author":"Kostrzewa","year":"2021","journal-title":"Cells"},{"key":"10.1016\/j.exger.2026.113316_bb0105","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.freeradbiomed.2025.08.033","article-title":"Epimedin B attenuates ovariectomy-induced bone loss by suppressing osteoclastogenesis through decreasing ROS production and targeting ESR1","volume":"240","author":"Lai","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0110","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S8756-3282(02)00971-7","article-title":"Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis","volume":"32","author":"Langdahl","year":"2003","journal-title":"Bone"},{"key":"10.1016\/j.exger.2026.113316_bb0115","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.trsl.2010.09.001","article-title":"Nicotine suppresses inflammatory factors in HBE16 airway epithelial cells after exposure to cigarette smoke extract and lipopolysaccharide","volume":"156","author":"Li","year":"2010","journal-title":"Transl. Res."},{"key":"10.1016\/j.exger.2026.113316_bb0120","doi-asserted-by":"crossref","DOI":"10.3892\/ijmm.2023.5311","article-title":"Arctiin attenuates iron overload-induced osteoporosis by regulating the PI3K\/Akt pathway","volume":"52","author":"Li","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0125","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.freeradbiomed.2025.09.014","article-title":"Cigarette smoke disrupts osteogenic-adipogenic balance via Nrf2\/HERC2 axis-driven ferroptosis","volume":"240","author":"Li","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0130","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s00198-004-1650-1","article-title":"Tests of linkage and\/or association of TGF-beta1 and COL1A1 genes with bone mass","volume":"16","author":"Long","year":"2005","journal-title":"Osteoporos. Int."},{"key":"10.1016\/j.exger.2026.113316_bb0135","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s12967-021-02836-z","article-title":"Cigarette smoke-associated inflammation impairs bone remodeling through NF\u03baB activation","volume":"19","author":"Lu","year":"2021","journal-title":"J. Transl. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0140","doi-asserted-by":"crossref","first-page":"30105","DOI":"10.1074\/jbc.M113.481309","article-title":"Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis","volume":"288","author":"Ma","year":"2013","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.exger.2026.113316_bb0145","doi-asserted-by":"crossref","DOI":"10.1016\/j.scitotenv.2020.141638","article-title":"Cadmium exposure triggers osteoporosis in duck via P2X7\/PI3K\/AKT-mediated osteoblast and osteoclast differentiation","volume":"750","author":"Ma","year":"2021","journal-title":"Sci. Total Environ."},{"key":"10.1016\/j.exger.2026.113316_bb0150","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.freeradbiomed.2018.01.017","article-title":"Nicotine induces apoptosis in human osteoblasts via a novel mechanism driven by H(2)O(2) and entailing Glyoxalase 1-dependent MG-H1 accumulation leading to TG2-mediated NF-kB desensitization: implication for smokers-related osteoporosis","volume":"117","author":"Marinucci","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"10.1016\/j.exger.2026.113316_bb0155","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20184331","article-title":"Molecular docking: shifting paradigms in drug discovery","volume":"20","author":"Pinzi","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.exger.2026.113316_bb0160","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.1007\/s00204-021-03123-y","article-title":"Systems toxicology study reveals reduced impact of heated tobacco product aerosol extract relative to cigarette smoke on premature aging and exacerbation effects in aged aortic cells in vitro","volume":"95","author":"Poussin","year":"2021","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.exger.2026.113316_bb0165","doi-asserted-by":"crossref","DOI":"10.1016\/j.tiv.2019.104664","article-title":"Mimicking cigarette smoke exposure to assess cutaneous toxicity","volume":"62","author":"Prieux","year":"2020","journal-title":"Toxicol. in Vitro"},{"key":"10.1016\/j.exger.2026.113316_bb0170","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s11011-014-9614-4","article-title":"Oxidative stress in the brain of cigarette smoke-induced noxiousness: neuroprotective role of Sesbania grandiflora","volume":"30","author":"Ramesh","year":"2015","journal-title":"Metab. Brain Dis."},{"key":"10.1016\/j.exger.2026.113316_bb0175","doi-asserted-by":"crossref","first-page":"5534","DOI":"10.1038\/s41380-025-03110-0","article-title":"Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks","volume":"30","author":"Reynolds","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"10.1016\/j.exger.2026.113316_bb0180","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bbrc.2008.09.114","article-title":"Nicotine induces cell proliferation in association with cyclin D1 up-regulation and inhibits cell differentiation in association with p53 regulation in a murine pre-osteoblastic cell line","volume":"377","author":"Sato","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"10.1016\/j.exger.2026.113316_bb0185","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15184525","article-title":"Vaping, environmental toxicants exposure, and lung cancer risk","volume":"15","author":"Shehata","year":"2023","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.exger.2026.113316_bb0190","doi-asserted-by":"crossref","DOI":"10.1016\/j.phymed.2024.156199","article-title":"The protective effects of medicinal plants against cigarette smoking: a comprehensive review","volume":"135","author":"Tabeshpour","year":"2024","journal-title":"Phytomedicine"},{"key":"10.1016\/j.exger.2026.113316_bb0195","article-title":"Nerve growth factor-loaded biomimetic prussian blue nanocomplexes for reversing osteoporosis via promoting osteoblast precursor cell proliferation and differentiation","volume":"32","author":"Tian","year":"2025","journal-title":"Mater. Today Bio"},{"key":"10.1016\/j.exger.2026.113316_bb0200","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhazmat.2025.137310","article-title":"H4K12 lactylation-regulated NLRP3 is involved in cigarette smoke-accelerated Alzheimer-like pathology through mTOR-regulated autophagy and activation of microglia","volume":"488","author":"Wang","year":"2025","journal-title":"J. Hazard. Mater."},{"key":"10.1016\/j.exger.2026.113316_bb0205","doi-asserted-by":"crossref","DOI":"10.3390\/genes13050806","article-title":"An overlooked bone metabolic disorder: cigarette smoking-induced osteoporosis","volume":"13","author":"Weng","year":"2022","journal-title":"Genes (Basel)"},{"key":"10.1016\/j.exger.2026.113316_bb0210","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41419-018-0540-y","article-title":"Artemether attenuates LPS-induced inflammatory bone loss by inhibiting osteoclastogenesis and bone resorption via suppression of MAPK signaling pathway","volume":"9","author":"Wu","year":"2018","journal-title":"Cell Death Dis."},{"key":"10.1016\/j.exger.2026.113316_bb0215","doi-asserted-by":"crossref","DOI":"10.1016\/j.ecoenv.2024.116392","article-title":"Tobacco toxins trigger bone marrow mesenchymal stem cells aging by inhibiting mitophagy","volume":"277","author":"Xiang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"10.1016\/j.exger.2026.113316_bb0220","article-title":"Electroacupuncture may protect pulmonary dysplasia in offspring with perinatal nicotine exposure by altering maternal gut microbiota and metabolites","volume":"15","author":"Xie","year":"2024","journal-title":"Front. Microbiol."},{"key":"10.1016\/j.exger.2026.113316_bb0225","doi-asserted-by":"crossref","DOI":"10.1016\/j.jep.2024.119023","article-title":"Exploring the osteogenic effects of simiao wan through activation of the PI3K\/AKT pathway in osteoblasts","volume":"338","author":"Xin","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"10.1016\/j.exger.2026.113316_bb0230","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1021\/acssensors.5c00275","article-title":"Engineering Bacillus spores to display nicotine oxidase: in situ specific and sensitive nicotine detection","volume":"10","author":"Xiong","year":"2025","journal-title":"ACS Sens."},{"key":"10.1016\/j.exger.2026.113316_bb0235","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s11658-019-0177-6","article-title":"MiR-135-5p promotes osteoblast differentiation by targeting HIF1AN in MC3T3-E1 cells","volume":"24","author":"Yin","year":"2019","journal-title":"Cell. Mol. Biol. Lett."},{"key":"10.1016\/j.exger.2026.113316_bb0240","article-title":"Advanced materials design for adsorption of toxic substances in cigarette smoke","volume":"10","author":"Zeng","year":"2023","journal-title":"Adv. Sci. (Weinh.)"},{"key":"10.1016\/j.exger.2026.113316_bb0245","doi-asserted-by":"crossref","DOI":"10.1016\/j.biomaterials.2025.123191","article-title":"Novel \u201chot spring\u201d-mimetic scaffolds for sequential neurovascular network reconstruction and osteoporosis reversion","volume":"320","author":"Zhao","year":"2025","journal-title":"Biomaterials"},{"key":"10.1016\/j.exger.2026.113316_bb0250","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.1007\/s00210-025-04783-8","article-title":"Unveiling the toxicological impact of cigarette smoke exposure on chronic obstructive pulmonary disease: integrated insights from network toxicology and multi-omics","volume":"399","author":"Zhou","year":"2025","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."}],"container-title":["Experimental Gerontology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0531556526002950?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0531556526002950?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:41:19Z","timestamp":1792428079000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0531556526002950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":50,"alternative-id":["S0531556526002950"],"URL":"https:\/\/doi.org\/10.1016\/j.exger.2026.113316","relation":{},"ISSN":["0531-5565"],"issn-type":[{"value":"0531-5565","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Integrative network toxicology, molecular docking, and in vitro experiments identify SLC6A2 as a novel candidate target in nicotine-induced osteoporosis","name":"articletitle","label":"Article Title"},{"value":"Experimental Gerontology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.exger.2026.113316","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"113316"}}