{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:02:19Z","timestamp":1790168539843,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Ischemic stroke remains a major cause of death and long-term disability despite reperfusion therapy. Tanshinone IIA (Tan IIA), a lipophilic diterpene quinone, and sodium tanshinone IIA sulfonate (STS), its water-soluble sulfonated derivative, show broad activity in experimental cerebral ischemia. They are often treated as interchangeable despite differences in formulation and exposure. We critically reviewed representative pharmacological, preclinical, formulation, and clinical evidence through 28 July 2026. We distinguished active entity, formulation, causal support, replication, exposure linkage, treatment window, and patient-centered relevance. Reported effects span oxidative and mitochondrial injury, endothelial barrier failure, neuroinflammation, regulated cell death, metabolism, and repair. Most pathway claims, however, rely on single laboratories, early dosing, young healthy rodents, short follow-up, or surrogate outcomes. Human evidence comprises one 42-patient STS-plus-rt-PA trial and a 2025 meta-analysis of 22 trials involving 2,289 participants. These findings suggest short-term signals but do not establish benefits for ordinal disability, survival, recurrent stroke, or uncommon bleeding. An injectable product and human plasma pharmacokinetic methods make STS more operationally tractable; superior efficacy remains unproven. Progression should require a fixed product, exposure-linked target engagement, durable benefit in aged and comorbid reperfusion models, and independent multicenter validation. Biological plausibility remains substantially stronger than translational readiness.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1959038","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:14:06Z","timestamp":1790165646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tanshinone IIA and sodium tanshinone IIA sulfonate in ischemic stroke: evidence, exposure, and translational readiness"],"prefix":"10.3389","volume":"19","author":[{"given":"Aiyue","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Neurology, The First People's Hospital of Linhai","place":["Taizhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Emergency and Intensive Care Medicine, The First People\u2019s Hospital of Linhai","place":["Taizhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Emergency and Intensive Care Medicine, The First People\u2019s Hospital of Linhai","place":["Taizhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangtian","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Emergency and Intensive Care Medicine, The First People\u2019s Hospital of Linhai","place":["Taizhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.2174\/0113895575299721240227070032","article-title":"Tanshinone IIA against cerebral ischemic stroke and ischemia-reperfusion injury: a review of the current documents","volume":"24","author":"Arefnezhad","year":"2024","journal-title":"Mini Rev. Med. Chem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1007\/s12975-021-00922-4","article-title":"PRIMED2 preclinical evidence scoring tool to assess readiness for translation of neuroprotection therapies","volume":"13","author":"Bahr-Hosseini","year":"2022","journal-title":"Transl. Stroke Res."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1089\/rej.2016.1912","article-title":"Tanshinone IIA elicits neuroprotective effect through activating the nuclear factor erythroid 2-related factor-dependent antioxidant response","volume":"20","author":"Cai","year":"2017","journal-title":"Rejuvenation Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/s41572-019-0118-8","article-title":"Ischaemic stroke","volume":"5","author":"Campbell","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e40165","DOI":"10.1371\/journal.pone.0040165","article-title":"Neuroprotection of tanshinone IIA against cerebral ischemia\/reperfusion injury through inhibition of macrophage migration inhibitory factor in rats","volume":"7","author":"Chen","year":"2012","journal-title":"PLoS One"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1080\/00498250701411258","article-title":"Role of P-glycoprotein in restricting the brain penetration of tanshinone IIA, a major active constituent from the root of Salvia miltiorrhiza Bunge, across the blood-brain barrier","volume":"37","author":"Chen","year":"2007","journal-title":"Xenobiotica"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.jneumeth.2011.01.010","article-title":"Long-term behavioral assessment of function in an experimental model for ischemic stroke","volume":"196","author":"Encarnacion","year":"2011","journal-title":"J. Neurosci. Methods"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1161\/STROKEAHA.108.541128","article-title":"Update of the stroke therapy academic industry roundtable preclinical recommendations","volume":"40","author":"Fisher","year":"2009","journal-title":"Stroke"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/S1474-4422(24)00369-7","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the global burden of disease study 2021","volume":"23","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s12975-023-01134-8","article-title":"A pilot systematic review and meta-analysis of neuroprotective studies in female rodent models of ischemic stroke","volume":"15","author":"Gunderson","year":"2024","journal-title":"Transl. Stroke Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/1934578X261430466","article-title":"Neuroprotective effects of tanshinone IIA from Salvia miltiorrhiza: mechanisms and advances in models of central nervous system injury","volume":"21","author":"Guo","year":"2026","journal-title":"Nat. Prod. Commun."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1007\/s12975-017-0526-6","article-title":"Sodium Tanshinone IIA sulfonate enhances effectiveness Rt-PA treatment in acute ischemic stroke patients associated with ameliorating blood-brain barrier damage","volume":"8","author":"Ji","year":"2017","journal-title":"Transl. Stroke Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1093\/stcltm\/szac062","article-title":"Tanshinone IIA-loaded nanoparticle and neural stem cell therapy enhances recovery in a pig ischemic stroke model","volume":"11","author":"Kaiser","year":"2022","journal-title":"Stem Cells Transl. Med."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"120413","DOI":"10.1016\/j.jep.2025.120413","article-title":"A systematic review and meta-analysis of randomized controlled trials on the efficacy and safety of tanshinone IIA sodium sulfonate injection as adjunctive therapy for stroke","volume":"353","author":"Liu","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1161\/STROKEAHA.121.038047","article-title":"The stroke preclinical assessment network: rationale, design, feasibility, and stage 1 results","volume":"53","author":"Lyden","year":"2022","journal-title":"Stroke"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3378","DOI":"10.1007\/s11064-023-03985-x","article-title":"Sodium tanshinone IIA sulfonate ameliorates oxygen-glucose deprivation\/reoxygenation-induced neuronal injury via protection of mitochondria and promotion of autophagy","volume":"48","author":"Ma","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1248\/cpb.55.753","article-title":"Ion-pair reversed-phase HPLC method for determination of sodium tanshinone IIA sulfonate in biological samples and its pharmacokinetics and biodistribution in mice","volume":"55","author":"Mao","year":"2007","journal-title":"Chem Pharm Bull (Tokyo)"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1161\/CIRCRESAHA.123.324139","article-title":"Biological and procedural predictors of outcome in the stroke preclinical assessment network (SPAN) trial","volume":"135","author":"Morais","year":"2024","journal-title":"Circ. Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1161\/STROKEAHA.122.040638","article-title":"Embracing heterogeneity in the multicenter stroke preclinical assessment network (SPAN) trial","volume":"54","author":"Morais","year":"2023","journal-title":"Stroke"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"10047","DOI":"10.1039\/D6TB01076H","article-title":"Tanshinone IIA nano-liposomes ameliorate cerebral ischemia-reperfusion injury associated with activation of the PGK1\/Nrf2 signalling axis","volume":"14","author":"Ou","year":"2026","journal-title":"J. Mater. Chem. B"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s11064-026-04817-4","article-title":"Neurochemical mechanisms underlying tanshinone-mediated neuroprotection and formulation strategies in cerebral ischemia\/reperfusion injury","volume":"51","author":"Park","year":"2026","journal-title":"Neurochem. Res."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e3000410","DOI":"10.1371\/journal.pbio.3000410","article-title":"The ARRIVE guidelines 2.0: updated guidelines for reporting animal research","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1161\/STR.0000000000000513","article-title":"2026 guideline for the early Management of Patients with Acute Ischemic Stroke: a guideline from the American Heart Association\/American Stroke Association","volume":"57","author":"Prabhakaran","year":"2026","journal-title":"Stroke"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.jpba.2016.01.026","article-title":"Determination of sodium tanshinone IIA sulfonate in human plasma by LC-MS\/MS and its application to a clinical pharmacokinetic study","volume":"121","author":"Qin","year":"2016","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"641848","DOI":"10.3389\/fphar.2021.641848","article-title":"Tanshinone IIA protects against cerebral ischemia reperfusion injury by regulating microglial activation and polarization via NF-\u03baB pathway","volume":"12","author":"Song","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.brainres.2012.09.034","article-title":"Neuroprotective effects of tanshinone IIA and\/or tetramethylpyrazine in cerebral ischemic injury in vivo and in vitro","volume":"1488","author":"Tang","year":"2012","journal-title":"Brain Res."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1016\/j.phymed.2010.03.017","article-title":"The effects of Tanshinone IIA on blood-brain barrier and brain edema after transient middle cerebral artery occlusion in rats","volume":"17","author":"Tang","year":"2010","journal-title":"Phytomedicine"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s11064-013-1221-y","article-title":"Protective effect of Tanshinone IIA against infarct size and increased HMGB1, NF-\u03baB, GFAP and apoptosis consequent to transient middle cerebral artery occlusion","volume":"39","author":"Wang","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"176","DOI":"10.5114\/fn.2020.96983","article-title":"Tanshinone IIA alleviates the damage of neurocytes by targeting GLUT1 in ischaemia reperfusion model (in vivo and in vitro experiments)","volume":"58","author":"Wang","year":"2020","journal-title":"Folia Neuropathol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.neuroscience.2020.05.054","article-title":"Sodium Tanshinone IIA sulfonate protects against cerebral ischemia-reperfusion injury by inhibiting autophagy and inflammation","volume":"441","author":"Wang","year":"2020","journal-title":"Neuroscience"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.ibneur.2020.11.003","article-title":"Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke","volume":"10","author":"Waters","year":"2021","journal-title":"IBRO Neurosci Rep"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3202","DOI":"10.1161\/STROKEAHA.123.044279","article-title":"Most promising approaches to improve stroke outcomes: the stroke treatment academic industry roundtable XII workshop","volume":"54","author":"Wechsler","year":"2023","journal-title":"Stroke"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"116772","DOI":"10.1016\/j.jep.2023.116772","article-title":"The protective effect of an extract of Salvia miltiorrhiza Bunge (Danshen) on cerebral ischemic injury in animal models: a systematic review and meta-analysis","volume":"317","author":"Xie","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.3892\/etm.2021.10556","article-title":"Sodium tanshinone IIA sulfonate ameliorates cerebral ischemic injury through regulation of angiogenesis","volume":"22","author":"Xu","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1159\/000325202","article-title":"Tanshinone IIA prevented brain iron dyshomeostasis in cerebral ischemic rats","volume":"27","author":"Yang","year":"2011","journal-title":"Cell. Physiol. Biochem."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1080\/03639045.2021.1908331","article-title":"Borneol-modified tanshinone IIA liposome improves cerebral ischemia reperfusion injury by suppressing NF-\u03baB and ICAM-1 expression","volume":"47","author":"Ye","year":"2021","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s11011-025-01660-4","article-title":"Tanshinone IIA inhibits neuronal ferroptosis and relieves cerebral ischemia-reperfusion injury by regulating miR-449a\/ACSL4","volume":"40","author":"Yu","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"5583","DOI":"10.1007\/s10528-025-11308-8","article-title":"Tanshinone IIA inhibits microglial activation and inflammation and relieves cerebral ischemia-reperfusion injury through TGM2\/PANX1","volume":"64","author":"Yu","year":"2026","journal-title":"Biochem. Genet."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.ejphar.2010.08.040","article-title":"Tanshinone IIA protects the human blood-brain barrier model from leukocyte-associated hypoxia-reoxygenation injury","volume":"648","author":"Zhang","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"106208","DOI":"10.1016\/j.neuint.2026.106208","article-title":"Tanshinone IIA alleviates cerebral ischemia-reperfusion injury by inhibiting pyroptosis: involvement of the KLF4\/CHIP\/NLRP3 pathway","volume":"199","author":"Zhong","year":"2026","journal-title":"Neurochem. Int."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"157548","DOI":"10.1016\/j.phymed.2025.157548","article-title":"Tanshinone IIA attenuates cerebral-ischemia-reperfusion-induced neuroinflammation by inhibiting the TLR4\/NF-\u03baB signaling cascade: a study integrating network pharmacology, bioinformatics, and experimental validation","volume":"149","author":"Zhou","year":"2025","journal-title":"Phytomedicine"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"109362","DOI":"10.1016\/j.biopha.2019.109362","article-title":"Sodium tanshinone IIA sulfonate: a review of pharmacological activity and pharmacokinetics","volume":"118","author":"Zhou","year":"2019","journal-title":"Biomed. Pharmacother."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1959038\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:14:07Z","timestamp":1790165647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2026.1959038\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":42,"alternative-id":["10.3389\/fnmol.2026.1959038"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2026.1959038","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"article-number":"1959038"}}