{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T20:16:33Z","timestamp":1788466593544,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"35","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2308085Y11"],"award-info":[{"award-number":["2308085Y11"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006247","name":"Anhui University of Science and Technology","doi-asserted-by":"publisher","award":["2023yjrc02"],"award-info":[{"award-number":["2023yjrc02"]}],"id":[{"id":"10.13039\/501100006247","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple myeloma (MM) is a malignant blood cancer marked by severe bone destruction and immune microenvironment disruption. Yet relapse and drug resistance remain major clinical challenges. Tanshinone IIA (TIIA) exhibits potent antitumor activity, but its molecular targets and mechanisms in MM remain unclear. Here, we systematically elucidate TIIA\u2019s pharmacological mechanisms in MM using network pharmacology, transcriptomics, molecular docking, molecular dynamics (MD) simulations, and in vitro cellular experiments. Histone deacetylase 6 (HDAC6) was identified as a key prognostic target in MM via integrative bioinformatics\u2500combining cross-database analysis, machine learning (LASSO, SVM-RFE, random forest), and survival validation in the MMRF-CoMMpass cohort. Molecular docking and MD simulations showed stable binding of TIIA to HDAC6. In vitro, TIIA directly inhibited HDAC6 enzymatic activity and selectively killed U266 and RPMI 8226 myeloma cells in a dose-dependent manner, with minimal toxicity to normal cells. Additionally, gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) immune profiling using the LM22 signature suggested that HDAC6 participates in microenvironmental remodeling by modulating cell adhesion-mediated resistance and orchestrating an immunosuppressive niche characterized by monocyte depletion. This study highlights for the first time the critical role of HDAC6 in TIIA-mediated antimyeloma activity and provides novel mechanistic insights and potential targeted therapeutic strategies for the treatment of MM.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c03788","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T22:01:33Z","timestamp":1788213693000},"page":"9007-9020","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning\nand Molecular Modeling Reveal HDAC6\nas a Key Target of Tanshinone IIA in Multiple Myeloma"],"prefix":"10.1021","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-0490","authenticated-orcid":true,"given":"Jian","family":"Gao","sequence":"first","affiliation":[{"name":"Anhui University of Science and Technology , , ,","place":["Huainan, China, 232001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Chu","sequence":"additional","affiliation":[{"name":"Anhui University of Science and Technology , , ,","place":["Huainan, China, 232001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengpeng","family":"Li","sequence":"additional","affiliation":[{"name":"Anhui University of Science and Technology , , ,","place":["Huainan, China, 232001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"8","key":"2026090315291806900_cit1","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1002\/ajh.26590","article-title":"Multiple\nmyeloma: 2022 update on diagnosis, risk stratification, and management","volume":"97","author":"Rajkumar","year":"2022","journal-title":"Am. J. Hematol."},{"issue":"3","key":"2026090315291806900_cit2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30756-7","article-title":"Treatment of relapsed\nand refractory multiple myeloma: recommendations from the International\nMyeloma Working Group","volume":"22","author":"Moreau","year":"2021","journal-title":"Lancet Oncol."},{"key":"2026090315291806900_cit3","doi-asserted-by":"publisher","first-page":"611087","DOI":"10.3389\/fphar.2020.611087","article-title":"Tanshinone IIA: A Review\nof its Anticancer Effects","volume":"11","author":"Fang","year":"2021","journal-title":"Front. Pharmacol."},{"issue":"6","key":"2026090315291806900_cit4","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1007\/s11373-006-9110-x","article-title":"Induction of apoptosis\nand inhibition of cell adhesive\nand invasive effects by tanshinone IIA in acute promyelocytic leukemia\ncells in vitro","volume":"13","author":"Liu","year":"2006","journal-title":"J. Biomed. Sci."},{"key":"2026090315291806900_cit5","doi-asserted-by":"publisher","first-page":"3372403","DOI":"10.1155\/2021\/3372403","article-title":"Tanshinone IIa Induces Autophagy\nand Apoptosis via PI3K\/Akt\/mTOR\nAxis in Acute Promyelocytic Leukemia NB4 Cells","volume":"2021","author":"Pan","year":"2021","journal-title":"Evid. Based Complement Alternat. Med."},{"key":"2026090315291806900_cit6","doi-asserted-by":"publisher","first-page":"805639","DOI":"10.1155\/2013\/805639","article-title":"Apoptosis\nInduced by Tanshinone IIA and Cryptotanshinone\nIs Mediated by Distinct JAK\/STAT3\/5 and SHP1\/2 Signaling in Chronic\nMyeloid Leukemia K562 Cells","volume":"2013","author":"Jung","year":"2013","journal-title":"J. Evidence-Based\nComplementary Altern. Med."},{"key":"2026090315291806900_cit7","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP:\na database of systems pharmacology for drug discovery from herbal\nmedicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"issue":"D1","key":"2026090315291806900_cit8","doi-asserted-by":"publisher","first-page":"D930","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."},{"issue":"W1","key":"2026090315291806900_cit9","doi-asserted-by":"publisher","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: updated data\nand new features for efficient prediction of protein targets of small\nmolecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"issue":"7","key":"2026090315291806900_cit10","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1002\/gcc.20668","article-title":"A SNP\nmicroarray and FISH-based procedure to detect\nallelic imbalances in multiple myeloma: an integrated genomics approach\nreveals a wide gene dosage effect","volume":"48","author":"Agnelli","year":"2009","journal-title":"Genes, Chromosomes\nCancer"},{"issue":"7","key":"2026090315291806900_cit11","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1158\/0008-5472.CAN-06-4046","article-title":"Molecular dissection of hyperdiploid multiple myeloma\nby gene expression profiling","volume":"67","author":"Chng","year":"2007","journal-title":"Cancer Res."},{"issue":"7","key":"2026090315291806900_cit12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing\nand microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"2026090315291806900_cit13","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data\nusing empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"issue":"1","key":"2026090315291806900_cit14","doi-asserted-by":"publisher","first-page":"7367328","DOI":"10.1155\/2022\/7367328","article-title":"Construction of MicroRNA-mRNA\nRegulatory Network in the Molecular Mechanisms of Bleomycin-Induced\nPulmonary Fibrosis","volume":"2022","author":"Chen","year":"2022","journal-title":"BioMed. Res. Int."},{"issue":"5","key":"2026090315291806900_cit15","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler:\nan R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2026090315291806900_cit16","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random Forests","volume":"45","author":"Breiman","journal-title":"Mach. Learn."},{"issue":"1","key":"2026090315291806900_cit17a","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1023\/A:1012487302797","article-title":"Gene Selection for Cancer Classification using Support\nVector Machines","volume":"46","author":"Guyon","year":"2002","journal-title":"Mach. Learn."},{"issue":"1","key":"2026090315291806900_cit17b","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression Shrinkage and Selection Via the Lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc."},{"issue":"6","key":"2026090315291806900_cit18","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting\ncancer genomics data via the Xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat. Biotechnol."},{"issue":"5","key":"2026090315291806900_cit19","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration\nof cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat. 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Engl. J. Med."},{"issue":"24","key":"2026090315291806900_cit24","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.1056\/NEJMoa043445","article-title":"Bortezomib or high-dose\ndexamethasone for relapsed multiple myeloma","volume":"352","author":"Richardson","year":"2005","journal-title":"N. Engl. J. 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Natl. Acad. Sci. U. S. A."},{"issue":"24","key":"2026090315291806900_cit30","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.1182\/blood.2020006540","article-title":"Cancer immunoediting and immune dysregulation\nin multiple myeloma","volume":"136","author":"Nakamura","year":"2020","journal-title":"Blood"},{"issue":"1","key":"2026090315291806900_cit31","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1111\/imr.12233","article-title":"Targeting the bone\nmarrow microenvironment in multiple myeloma","volume":"263","author":"Kawano","year":"2015","journal-title":"Immunol Rev."},{"issue":"1","key":"2026090315291806900_cit32a","doi-asserted-by":"publisher","first-page":"6136","DOI":"10.1038\/s41598-019-42237-3","article-title":"Selective\nHDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy\nby decreasing the anti-inflammatory phenotype of macrophages and down-regulation\nof immunosuppressive proteins in tumor cells","volume":"9","author":"Knox","year":"2019","journal-title":"Sci. Rep."},{"issue":"1","key":"2026090315291806900_cit32b","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s40425-019-0517-0","article-title":"HDAC6 selective\ninhibition of melanoma patient T-cells augments anti-tumor characteristics","volume":"7","author":"Laino","year":"2019","journal-title":"J. Immunother Cancer"},{"issue":"3","key":"2026090315291806900_cit33","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/leu.2008.336","article-title":"Pathogenesis\nof myeloma bone disease","volume":"23","author":"Roodman","year":"2009","journal-title":"Leukemia"},{"issue":"2","key":"2026090315291806900_cit34","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1182\/blood-2012-02-412783","article-title":"Drug response in a genetically engineered\nmouse model\nof multiple myeloma is predictive of clinical efficacy","volume":"120","author":"Chesi","year":"2012","journal-title":"Blood"}],"container-title":["The Journal of Physical\nChemistry B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpcb.6c03788","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/35\/9007\/67394034\/acs.jpcb.6c03788.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/35\/9007\/67394034\/acs.jpcb.6c03788.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T19:29:28Z","timestamp":1788463768000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article\/130\/35\/9007\/5328302\/Machine-Learning-and-Molecular-Modeling-Reveal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":36,"journal-issue":{"issue":"35","published-online":{"date-parts":[[2026,8,25]]},"published-print":{"date-parts":[[2026,9,3]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpcb.6c03788","relation":{},"ISSN":["1520-6106","1520-5207"],"issn-type":[{"value":"1520-6106","type":"print"},{"value":"1520-5207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}