{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:11Z","timestamp":1790661911146,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023B1515120081"],"award-info":[{"award-number":["2023B1515120081"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2023A1515110287"],"award-info":[{"award-number":["2023A1515110287"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274539"],"award-info":[{"award-number":["82274539"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background and objective<\/jats:title>\n                    <jats:p>Lumbar spinal stenosis is a prevalent degenerative disorder driven primarily by ligamentum flavum hypertrophy. Emerging evidence links ectopic lipid accumulation to fibrotic remodeling and suggests a potential contribution of immune dysregulation. However, the molecular targets connecting lipid accumulation with ligamentum flavum fibrosis remain incompletely defined. We sought to evaluate the underlying mechanisms of lipid-lowering drug targets in lipid-associated ligamentum flavum fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We applied two-sample Mendelian randomization (MR), summary-data-based MR, and Bayesian colocalization to evaluate the associations of genetically proxied levels of 213 lipid-lowering drug target proteins with lumbar spinal stenosis risk. Candidate targets were evaluated\n                      <jats:italic>via<\/jats:italic>\n                      genetic immune-cell mediation analysis, molecular docking, molecular dynamics simulations, and experimental validation\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR identified three proteins increasing disease risk, with placental alkaline phosphatase (ALPP) consistently replicating across platforms (colocalization at rs12478529, PP.H4 = 0.9979). Genetically inferred mediation analysis suggested that selected immune-cell traits may partially mediate the association between ALPP and lumbar spinal stenosis. Molecular dynamics simulations and cellular thermal shift assays supported target engagement of atorvastatin and simvastatin with ALPP. In clinical specimens, ALPP was upregulated in hypertrophied tissues, co-localizing with fibrosis and lipid accumulation.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , statins suppressed lipid accumulation and fibrotic markers; ALPP overexpression counteracted these protective effects.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , systemic statin administration attenuated ligamentum flavum thickening, whereas local viral-mediated ALPP overexpression reversed this benefit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify ALPP as a genetically supported candidate associated with LSS and link it to lipid accumulation and fibrosis. Computational and CETSA findings support possible target engagement of statins with ALPP and attenuate lipid accumulation and fibrosis, supporting ALPP as a potential mediator of their effects and statin repurposing for LSS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1910904","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:35Z","timestamp":1790660795000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Placental alkaline phosphatase promotes lipid accumulation and fibrosis in ligamentum flavum hypertrophy and represents a potential target for statin repurposing"],"prefix":"10.3389","volume":"17","author":[{"given":"Junjie","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Spine Surgery, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konghe","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, The Affiliated Yuebei People\u2019s Hospital of Shantou University Medical College","place":["Shaoguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanbin","family":"Lin","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runfan","family":"Chen","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxiong","family":"Min","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Spine Surgery, Department of Spine Surgery, Peking University Shenzhen Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, Zhujiang Hospital, Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Crp Chd Genetics Collaboration. Avoiding bias from weak instruments in mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s13062-023-00436-z","article-title":"ACSM5 inhibits ligamentum flavum hypertrophy by regulating lipid accumulation mediated by FABP4\/PPAR signaling pathway","volume":"18","author":"Cao","year":"","journal-title":"Biol. Direct"},{"key":"B4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13062-023-00383-9","article-title":"LncRNA XIST facilitates hypertrophy of ligamentum flavum by activating VEGFA-mediated autophagy through sponging miR-302b-3p","volume":"18","author":"Cao","year":"","journal-title":"Biol. Direct"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e13534","DOI":"10.1111\/eci.13534","article-title":"The role of statins in the differentiation and function of bone cells","volume":"51","author":"Chamani","year":"2021","journal-title":"Eur. J. Clin. Invest"},{"key":"B6","doi-asserted-by":"publisher","first-page":"120957","DOI":"10.1016\/j.jep.2025.120957","article-title":"Duhuo Jisheng decoction alleviates intervertebral disc degeneration by inhibiting nucleus pulposus cell pyroptosis via gallic acid-mediated downregulation of HIF-1\u03b1","volume":"358","author":"Cheng","year":"2026","journal-title":"J. Ethnopharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"115644","DOI":"10.1016\/j.bcp.2023.115644","article-title":"Anti-fibrotic effects of statin drugs: a review of evidence and mechanisms","volume":"214","author":"Dolivo","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1186\/s12967-022-03677-0","article-title":"TCF7\/SNAI2\/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum","volume":"20","author":"Duan","year":"2022","journal-title":"J. Transl. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e38782","DOI":"10.1097\/MD.0000000000038782","article-title":"Nonsurgical therapy for lumbar spinal stenosis caused by ligamentum flavum hypertrophy: a review","volume":"103","author":"Fang","year":"2024","journal-title":"Med. Baltim."},{"key":"B10","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41389-025-00589-8","article-title":"Stabilization of FASN by USP5-mediated deubiquitination promotes hepatocellular carcinoma progression","volume":"14","author":"Fang","year":"2025","journal-title":"Oncogenesis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/s41588-020-0622-5","article-title":"Exploring and visualizing large-scale genetic associations using PheWeb","volume":"52","author":"Gagliano Taliun","year":"2020","journal-title":"Nat. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1004383","DOI":"10.1371\/journal.pgen.1004383","article-title":"Bayesian test for colocalisation between pairs of genetic association studies using summary statistics","volume":"10","author":"Giambartolomei","year":"2014","journal-title":"PLOS Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"B15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.freeradbiomed.2025.12.033","article-title":"Atorvastatin alleviates the progression of fibrosis in experimental systemic sclerosis: binding to macrophage CD14 to regulate TLR4\/p65 or directly modulating fibroblast Smad3 signaling","volume":"245","author":"Hu","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1038\/nrd1901","article-title":"Anti-inflammatory effects of statins: clinical evidence and basic mechanisms","volume":"4","author":"Jain","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1001\/jama.2022.5921","article-title":"Diagnosis and management of lumbar spinal stenosis: a review","volume":"327","author":"Katz","year":"2022","journal-title":"JAMA"},{"key":"B18","doi-asserted-by":"publisher","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: new data content and improved web interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"135","DOI":"10.2174\/1871530317666171116115120","article-title":"Statins therapy for connective tissue diseases: new therapeutic opportunities","volume":"18","author":"Kotyla","year":"2018","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"B20","doi-asserted-by":"publisher","first-page":"eaao0303","DOI":"10.1126\/scitranslmed.aao0303","article-title":"PPAR\u03b3 agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation","volume":"10","author":"Legchenko","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1002\/prot.22711","article-title":"Improved side-chain torsion potentials for the amber ff99SB protein force field","volume":"78","author":"Lindorff-Larsen","year":"2010","journal-title":"Proteins"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1038\/s12276-022-00849-2","article-title":"Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-\u03b21 signaling","volume":"54","author":"Liu","year":"","journal-title":"Exp. Mol. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Liu","year":"","journal-title":"Nucleic Acids Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1002\/jcc.22885","article-title":"Multiwfn: a multifunctional wavefunction analyzer","volume":"33","author":"Lu","year":"2012","journal-title":"J. Comput. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1126\/science.1233606","article-title":"Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay","volume":"341","author":"Martinez Molina","year":"2013","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","first-page":"D931","DOI":"10.1093\/nar\/gky1075","article-title":"ChEMBL: towards direct deposition of bioassay data","volume":"47","author":"Mendez","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1161\/ATV.0000000000000073","article-title":"Statin safety and associated adverse events: a scientific statement from the American heart association","volume":"39","author":"Newman","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4950","DOI":"10.3390\/ijms22094950","article-title":"Effects of simvastatin on lipid metabolism in wild-type mice and mice with muscle PGC-1\u03b1 overexpression","volume":"22","author":"Panajatovic","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.bbi.2019.09.013","article-title":"Lovastatin inhibits toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain","volume":"82","author":"Peng","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"B30","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1093\/bioinformatics\/btt055","article-title":"GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit","volume":"29","author":"Pronk","year":"2013","journal-title":"Bioinformatics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7397","DOI":"10.3390\/jcm13237397","article-title":"Association between higher body mass index and the risk of lumbar spinal stenosis in korean populations: a nationwide cohort study","volume":"13","author":"Ryu","year":"2024","journal-title":"J. Clin. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7691","DOI":"10.3390\/jcm14217691","article-title":"Long-term and heavy smoking as a risk factor for lumbar spinal stenosis: evidence from a large-scale, nationwide population-based cohort","volume":"14","author":"Ryu","year":"2025","journal-title":"J. Clin. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1896","DOI":"10.1097\/HEP.0000000000000278","article-title":"Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC","volume":"78","author":"Sharpton","year":"2023","journal-title":"Hepatology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1097\/BRS.0000000000004900","article-title":"Diabetes mellitus and poor glycemic control are associated with a higher risk of lumbar spinal stenosis: an analysis of a large nationwide database","volume":"49","author":"Shemesh","year":"2024","journal-title":"Spine"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1172\/JCI28898","article-title":"TLR4 links innate immunity and fatty acid-induced insulin resistance","volume":"116","author":"Shi","year":"2006","journal-title":"J. Clin. Invest"},{"key":"B36","doi-asserted-by":"publisher","first-page":"557","DOI":"10.2307\/2171753","article-title":"Instrumental variables regression with weak instruments","volume":"65","author":"Staiger","year":"1997","journal-title":"Econometrica"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e198647","DOI":"10.1172\/jci.insight.198647","article-title":"Atorvastatin suppresses HIV\/antiretroviral drug-induced cardiac fibrosis and dysfunction in mice by blocking platelet TGF\u03b21 signaling","volume":"11","author":"Subramani","year":"2026","journal-title":"JCI Insight"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1038\/s12276-021-00636-5","article-title":"WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through hedgehog-Gli1 signaling","volume":"53","author":"Sun","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1007\/s11010-022-04621-y","article-title":"Facts and ideas on statins with respect to their lipophilicity: a focus on skeletal muscle cells and bone besides known cardioprotection","volume":"478","author":"Svec","year":"2023","journal-title":"Mol. Cell Biochem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"306","DOI":"10.22603\/ssrr.2022-0081","article-title":"The essence of clinical practice guidelines for lumbar spinal stenosis, 2021: 3. Conservative treatment","volume":"7","author":"Takeshita","year":"2023","journal-title":"Spine Surg. Relat. Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: a new tool to perform end-state free energy calculations with GROMACS","volume":"17","author":"Vald\u00e9s-Tresanco","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"B43","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41586-021-03855-y","article-title":"Rare variant contribution to human disease in 281,104 UK biobank exomes","volume":"597","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: a major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"556022","DOI":"10.3389\/fmed.2021.556022","article-title":"Investigating research hotspots and publication trends of spinal stenosis: a bibliometric analysis during 2000\u20132018","volume":"8","author":"Yang","year":"2021","journal-title":"Front. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"103320","DOI":"10.1016\/j.drudis.2022.07.005","article-title":"Statins and angiogenesis in non-cardiovascular diseases","volume":"27","author":"Zahedipour","year":"2022","journal-title":"Drug Discov. Today"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2877","DOI":"10.1007\/s00204-025-04056-6","article-title":"Key genes and processes affected by atorvastatin treatment in mouse diaphragm muscle","volume":"99","author":"Zakyrjanova","year":"2025","journal-title":"Arch. Toxicol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1038\/s12276-024-01348-2","article-title":"Noncoding RNA as a crucial epigenetic modulator in the degeneration of the ligamentum flavum","volume":"56","author":"Zhao","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2457","DOI":"10.1111\/os.13156","article-title":"Characterization of a novel model of Lumbar Ligamentum Flavum Hypertrophy in bipedal standing mice","volume":"13","author":"Zheng","year":"2021","journal-title":"Orthop. Surg."},{"key":"B50","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41591-021-01281-1","article-title":"A neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity","volume":"27","author":"Zhou","year":"2021","journal-title":"Nat. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1910904\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:46:37Z","timestamp":1790660797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1910904\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":51,"alternative-id":["10.3389\/fphar.2026.1910904"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1910904","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]},"article-number":"1910904"}}