Cryptotanshinone

Cryptotanshinone at a Glance

Cryptotanshinone is one of the four tanshinones — the orange-red, fat-soluble abietane diterpene quinones that give dan shen root its colour and half its pharmacology. Chemically it is C₁₉H₂₀O₃, 296 Da, an ortho-quinone carrying a dihydrofuran D-ring with a single stereocentre; formally it is 15,16-dihydrotanshinone IIA, two hydrogens away from its more famous sibling. That relationship is not cosmetic. Cryptotanshinone oxidises to tanshinone IIA in solvent, and about a fifth of an oral dose is converted to it in a rat ^{26,27Reference 26Roth A et al. · 2023In vitroChemical stability and bioactivity of tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone in in vitro test systems — analytical and in vitro studyView study →Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}. A large share of what is written about “cryptotanshinone” therefore has a second molecule standing behind it.

Its reputation rests on a single claim: that it is a direct inhibitor of STAT3, the transcription factor constitutively active in most solid tumours and one of the most sought-after and least drugged targets in oncology. That claim is real, widely cited, and worth taking apart carefully — which is what the next section does — because STAT3 is also the single most promiscuous target in natural-product pharmacology, and cryptotanshinone is a redox-active quinone.

Underneath the headline there is a genuinely good molecule. It antagonises the androgen receptor at sub-micromolar concentrations with demonstrated selectivity against ERα, GR and PR ^{10Reference 10Xu D et al. · 2012In vitroCryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells — in vitro and xenograft studyView study →}. It is a specific NLRP3 inflammasome inhibitor that spares AIM2 and NLRC4 ^{19Reference 19Liu H et al. · 2021In vitroCryptotanshinone specifically suppresses NLRP3 inflammasome activation and protects against inflammasome-mediated diseases — in vitro and mouse in vivo studyView study →}. It kills Gram-positive bacteria including MRSA ^{21,22,24Reference 21Lee DS et al. · 1999In vitroAntibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge — in vitro studyView study →Reference 22Zhong J et al. · 2021In vitroIdentification of the antibacterial mechanism of cryptotanshinone on methicillin-resistant Staphylococcus aureus using bioinformatics analysis — in vitro studyView study →Reference 24Liu Q et al. · 2025In vitroCryptotanshinone targets the bacterial membrane and inhibits methicillin-resistant Staphylococcus aureus — in vitro studyView study →}, and it has a rat polycystic ovary syndrome literature large enough to have been formally meta-analysed ^{17Reference 17Su P et al. · 2025Meta-analysisEffects of cryptotanshinone in treatment of polycystic ovary syndrome in rats: a systematic review and meta-analysis — animal-model meta-analysis of 7 studiesView study →}. What it does not have is a single human being who has taken it. Oral bioavailability in rats is 2.1% ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}, the registered human PCOS trial tested a mixed tanshinone preparation rather than the molecule and never reported results ^{18Reference 18Heilongjiang University of Chinese Medic · 2011RCTEffect of tanshinone on hormonal and metabolic features in women with polycystic ovary syndrome (PCOS) — randomised, quadruple-blind, placebo-controlled trial; status UNKNOWN since 2013, no results postedView study →}, and there is no toxicology package for the isolate at all.

The STAT3 Claim, Examined

Search cryptotanshinone AND STAT3 and PubMed returns 126 records. Almost all of them cite one paper. It is worth knowing exactly what that paper did.

What the Primary Evidence Actually Is

Shin and colleagues at the Korea Research Institute of Bioscience and Biotechnology screened natural compounds in a dual-luciferase STAT3 reporter assay and pulled out cryptotanshinone ^{3Reference 3Shin DS et al. · 2009In vitroCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro studyView study →}. In DU145 prostate cancer cells it inhibited STAT3 Tyr705 phosphorylation within 30 minutes and suppressed the downstream proteins cyclin D1, survivin and Bcl-xL. Crucially, JAK2 phosphorylation was only inhibited at 7 µM after 24 hours — far too slow to explain the 30-minute effect — so the authors concluded the mechanism was JAK2-independent, with JAK2 suppression a secondary consequence ^{3Reference 3Shin DS et al. · 2009In vitroCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro studyView study →}.

Then comes the part everybody quotes and few read precisely. The paper reports that cryptotanshinone colocalised with STAT3 in the cytoplasm, that it inhibited formation of STAT3 dimers, and that computational modelling showed it could bind the SH2 domain ^{3Reference 3Shin DS et al. · 2009In vitroCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro studyView study →}. The authors’ own wording is hedged — the experiments “revealed the possibility that cryptotanshinone might directly bind to STAT3 molecules.”

That is the whole primary basis for “direct STAT3 inhibitor.” A reporter screen, a rapid dephosphorylation, colocalisation, a dimerisation readout, and a docking pose.

What Is Missing

No binding constant for cryptotanshinone and STAT3 has been published. No surface plasmon resonance, no isothermal titration calorimetry, no biolayer interferometry, no measured Kd. A docking pose is a hypothesis about binding, not a measurement of it.

Selectivity against the other STATs was never tested in the primary paper. STAT1 and STAT5 are structurally close and are the standard controls; neither appears in Shin’s experiments ^{3Reference 3Shin DS et al. · 2009In vitroCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro studyView study →}.

Both gaps are instructive because the medicinal-chemistry field went on to fill them — for a synthetic derivative, not for the natural product. Wang and colleagues used a structure-based strategy to “remodel the natural compound cryptotanshinone into a more effective STAT3 inhibitor,” produced LYW-6, and then did the work: biolayer interferometry gave a Kd of 6.6 ± 0.7 µM, and Western blotting confirmed the compound hit STAT3 Tyr705 with only slight effects on STAT1 and STAT5 ^{5Reference 5Wang H et al. · 2020AnimalLYW-6, a novel cryptotanshinone derived STAT3 targeting inhibitor, suppresses colorectal cancer growth and metastasis — medicinal chemistry and in vivo studyView study →}. The measured affinity and the selectivity data in this lineage belong to the analogue. The premise of that paper — that the parent needed remodelling to be effective — is itself a verdict on the parent.

The Competing Explanation

A second laboratory reproduced the phenotype and assigned it a different, indirect mechanism. Lu and colleagues found that in glioma cells cryptotanshinone increased the tyrosine phosphatase activity of SHP-2 in a dose-dependent manner, and that an SHP-2 inhibitor or SHP-2 siRNA reversed cryptotanshinone’s inhibition of STAT3 Tyr705 phosphorylation ^{4Reference 4Lu L et al. · 2017In vitroCryptotanshinone inhibits human glioma cell proliferation in vitro and in vivo through SHP-2-dependent inhibition of STAT3 activation — in vitro and mouse xenograft studyView study →}. If the phosphatase is required for the effect, the effect is not simple occupancy of the SH2 domain.

And STAT3 is not even the only “the” mechanism on offer. In the same literature cryptotanshinone has been reported to work through:

• mTOR/cyclin D1/Rb, with constitutively active mTOR conferring resistance — an explicitly mTOR-dependent account that does not invoke STAT3 at all ^{6Reference 6Chen W et al. · 2010In vitroCryptotanshinone inhibits cancer cell proliferation by suppressing mammalian target of rapamycin-mediated cyclin D1 expression and Rb phosphorylation — in vitro studyView study →}
• mTORC1–S6K1, by preventing S6K1 from binding the mTOR/Raptor complex ^{8Reference 8Jeoung NH et al. · 2021In vitroCryptotanshinone prevents the binding of S6K1 to mTOR/Raptor leading to the suppression of mTORC1-S6K1 signaling activity and neoplastic cell transformation — in vitro studyView study →}
• the AMPK–TSC2 axis upstream of mTORC1 ^{9Reference 9Chen W et al. · 2017In vitroCryptotanshinone activates AMPK-TSC2 axis leading to inhibition of mTORC1 signaling in cancer cells — in vitro studyView study →}
• oestrogen receptor α, with ERα-negative breast cancer cells simply insensitive and ERα knockdown abolishing the mTOR effect ^{7Reference 7Pan Y et al. · 2017In vitroCryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer — in vitro studyView study →}
• NQO1, driving a non-enzymatic necrosis through JNK1/2, iron, PARP and calcium ^{46Reference 46Hou Y et al. · 2025In vitroA small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/iron/PARP/calcium pathway — in vitro and in vivo studyView study →}

How to Read It

The honest position is not that the STAT3 story is wrong. Tyr705 dephosphorylation is reproducible across many laboratories and cell types, the downstream consequences are consistent, and the xenograft data are real. The honest position is about what kind of claim it is:

Cryptotanshinone reliably suppresses STAT3 signalling. Whether it does so by binding STAT3 is unresolved, and the evidence offered for direct binding — docking plus colocalisation — is the weakest tier of evidence for that specific proposition. Anyone quoting “direct STAT3 inhibitor” as an established molecular fact is over-reading the source. Anyone dismissing the pharmacology because the binding is unproven is under-reading it.

The Dihydrofuran That Becomes Tanshinone IIA

Cryptotanshinone differs from tanshinone IIA by a single saturated bond. Under oxidising conditions it loses two hydrogens and becomes it — and this happens in three different places, each with a different consequence.

In the assay. Roth and colleagues at the German Sport University and the Max Rubner-Institut ran a purity-and-stability check on all four tanshinones before testing them, and found that cryptotanshinone and dihydrotanshinone I decreased rapidly in DMSO and were converted to tanshinone IIA and tanshinone I respectively; in aqueous solution the concentration of every tanshinone fell over 24 hours ^{26Reference 26Roth A et al. · 2023In vitroChemical stability and bioactivity of tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone in in vitro test systems — analytical and in vitro studyView study →}. DMSO is the standard vehicle for these compounds. Their conclusion — that tanshinone I and tanshinone IIA “are the most relevant bioactive tanshinones in Danshen,” and that the instability of the others “is relevant when discussing their potential therapeutic benefits” — is a warning that some published cryptotanshinone activity may belong to the oxidation product it silently became in the stock vial ^{26Reference 26Roth A et al. · 2023In vitroChemical stability and bioactivity of tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone in in vitro test systems — analytical and in vitro studyView study →}.

In the animal. This is not merely an artefact. Song and colleagues dosed rats with cryptotanshinone alone and measured tanshinone IIA appearing in plasma, with a fraction metabolised to tanshinone IIA of 21.0 ± 4.1% ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}. A 2012 review notes the same biotransformation in pig and rat ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}. So roughly a fifth of an oral cryptotanshinone dose acts as tanshinone IIA in vivo, and formulation changes the split — solid lipid nanoparticles that raised cryptotanshinone’s oral exposure also “markedly changed the metabolism behaviour of CTS to tanshinone IIA” ^{37Reference 37Hu L et al. · 2010AnimalPreparation and enhanced oral bioavailability of cryptotanshinone-loaded solid lipid nanoparticles — rat pharmacokinetic studyView study →}.

In the plant and the product. Both molecules are present in the root at similar levels (764 vs 895 mg/kg ^{38Reference 38Ayvazyan A et al. · 2023Cytotoxic diterpenoids from Salvia glutinosa and comparison with the tanshinone profile of danshen (Salvia miltiorrhiza) — UHPLC-DAD-MS quantificationView study →}), and both degrade with heat, light and time in the same way carnosic acid does in rosemary — the batch’s other instability story, told on carnosic acid and carnosol.

The practical consequence runs one way only. A cryptotanshinone finding may be partly a tanshinone IIA finding; a tanshinone IIA finding is not a cryptotanshinone finding, because the reaction does not run backwards. Where an activity is reported, it is reported as measured, with the conversion caveat standing over the whole set.

Which Danshen Preparation Delivers It

Dan shen is chemically two herbs sharing a root, and cryptotanshinone sits squarely on one side of the divide.

• The lipophilic tanshinone fraction — tanshinone IIA, cryptotanshinone, tanshinone I, dihydrotanshinone I — is extracted by ethanol or supercritical CO₂ and is essentially insoluble in water.
• The hydrophilic fraction — the salvianolic acids, chiefly salvianolic acid B and salvianolic acid A, and their precursor rosmarinic acid — is what a water decoction pulls out.

The analytical literature is blunt about what this means for traditional use: in the conventional preparation of danshen decocted by water, only a trace of tanshinones could be obtained ^{39Reference 39Pang H et al. · 2016ReviewChemical analysis of the herbal medicine Salviae miltiorrhizae Radix et Rhizoma (danshen) — analytical reviewView study →}. The Chinese Pharmacopoeia’s marker specification reflects the same split — the dried root must meet a combined floor for tanshinone IIA, cryptotanshinone and tanshinone I on one side and a separate salvianolic acid B floor on the other ^{39,45Reference 39Pang H et al. · 2016ReviewChemical analysis of the herbal medicine Salviae miltiorrhizae Radix et Rhizoma (danshen) — analytical reviewView study →Reference 45Su CY et al. · 2015ReviewSalvia miltiorrhiza: traditional medicinal uses, chemistry, and pharmacology — reviewView study →}.

So: if you drink dan shen as a tea, you are not meaningfully taking cryptotanshinone. The molecule reaches people through ethanolic extracts, standardised “total tanshinone” products and topical acne preparations. One further discipline belongs here, because it governs how the sibling literature is read: tanshinone IIA sodium sulfonate, the water-soluble injectable used clinically in China, is a semi-synthetic derivative. Its trial data belong to neither tanshinone IIA nor cryptotanshinone.

What It's Used For

Cryptotanshinone has a substantial literature — 898 PubMed records, of which 508 also mention Salvia miltiorrhiza, an unusually clean attribution for a plant molecule. Two general reviews collate it ^{1,2Reference 1Li H et al. · 2021ReviewA review of the biological activity and pharmacology of cryptotanshinone, an important active constituent in Danshen — reviewView study →Reference 2Wu YH et al. · 2020ReviewCryptotanshinone: a review of its pharmacology activities and molecular mechanisms — reviewView study →}. The shape of the evidence is consistent across every application below: purified molecule, cell and rodent models, doses in the tens of mg/kg, no human isolate data anywhere.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. Every row shares two ceilings: nobody has taken this molecule under study conditions, and part of any dose is tanshinone IIA by the time it acts.

01Anti-inflammatoryShaky44%Specific NLRP3 inhibition with AIM2/NLRC4 controls, plus colitis, COPD and asthma rodent models ^{19,20,47,48Reference 19Liu H et al. · 2021In vitroCryptotanshinone specifically suppresses NLRP3 inflammasome activation and protects against inflammasome-mediated diseases — in vitro and mouse in vivo studyView study →Reference 20Gao H et al. · 2018In vitroSimultaneous purification of dihydrotanshinone, tanshinone I, cryptotanshinone, and tanshinone IIA from Salvia miltiorrhiza and their anti-inflammatory activities investigation — in vitro and animal modelView study →Reference 47Song H et al. · 2023AnimalCryptotanshinone alleviates lipopolysaccharide and cigarette smoke-induced chronic obstructive pulmonary disease in mice via the Keap1/Nrf2 axis — mouse in vivo studyView study →Reference 48Fan LM et al. · 2022AnimalCryptotanshinone ameliorates dextran sulfate sodium-induced murine acute and chronic ulcerative colitis via suppressing STAT3 activation and Th17 cell differentiation — mouse in vivo studyView study →}

02Prostate — AR antagonism & BPHShaky40%Sub-micromolar, receptor-selective AR inhibition, two independent mechanisms, xenograft and BPH rat data ^{10,11,12Reference 10Xu D et al. · 2012In vitroCryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells — in vitro and xenograft studyView study →Reference 11Wu CY et al. · 2012In vitroCryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function — in vitro studyView study →Reference 12Wei P et al. · 2023In vitroCryptotanshinone modulates proliferation, apoptosis, and fibrosis through inhibiting AR and EGFR/STAT3 axis to ameliorate benign prostatic hyperplasia progression — in vitro and rat studyView study →}

03PCOS & hyperandrogenismShaky36%Seven concordant rat studies, formally meta-analysed; one registered human trial of a mixed preparation, unreported ^{13,14,15,16,17,18Reference 13Yang X et al. · 2011AnimalCryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of ovarian signaling mechanisms and androgen synthesis — rat in vivo studyView study →Reference 14Yu J et al. · 2014AnimalCryptotanshinone reverses reproductive and metabolic disturbances in PCOS model rats via regulating the expression of CYP17 and AR — rat in vivo studyView study →Reference 15Huang Y et al. · 2014AnimalCryptotanshinone reverses ovarian insulin resistance in mice through activation of insulin signaling and the regulation of glucose transporters and hormone synthesizing enzymes — mouse in vivo studyView study →Reference 16Ye D et al. · 2017In vitroCryptotanshinone regulates androgen synthesis through the ERK/c-Fos/CYP17 pathway in porcine granulosa cells — in vitro studyView study →Reference 17Su P et al. · 2025Meta-analysisEffects of cryptotanshinone in treatment of polycystic ovary syndrome in rats: a systematic review and meta-analysis — animal-model meta-analysis of 7 studiesView study →Reference 18Heilongjiang University of Chinese Medic · 2011RCTEffect of tanshinone on hormonal and metabolic features in women with polycystic ovary syndrome (PCOS) — randomised, quadruple-blind, placebo-controlled trial; status UNKNOWN since 2013, no results postedView study →}

04Antibacterial (Gram-positive, MRSA, acne)Shaky32%1999 mechanism paper plus modern MRSA membrane and antibiotic-synergy work; a rat acne model ^{21,22,23,24,25Reference 21Lee DS et al. · 1999In vitroAntibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge — in vitro studyView study →Reference 22Zhong J et al. · 2021In vitroIdentification of the antibacterial mechanism of cryptotanshinone on methicillin-resistant Staphylococcus aureus using bioinformatics analysis — in vitro studyView study →Reference 23Cha JD et al. · 2014In vitroSynergistic effect between cryptotanshinone and antibiotics against clinic methicillin and vancomycin-resistant Staphylococcus aureus — in vitro studyView study →Reference 24Liu Q et al. · 2025In vitroCryptotanshinone targets the bacterial membrane and inhibits methicillin-resistant Staphylococcus aureus — in vitro studyView study →Reference 25Zhu Z et al. · 2022AnimalSkin microbiome reconstruction and lipid metabolism profile alteration reveal the treatment mechanism of cryptotanshinone in the acne rat — rat in vivo studyView study →}

05Anticancer (STAT3 and everything else)Shaky28%Very large cell literature, several xenografts — and no agreed mechanism ^{3,4,5,6,7,8,9,46Reference 3Shin DS et al. · 2009In vitroCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro studyView study →Reference 4Lu L et al. · 2017In vitroCryptotanshinone inhibits human glioma cell proliferation in vitro and in vivo through SHP-2-dependent inhibition of STAT3 activation — in vitro and mouse xenograft studyView study →Reference 5Wang H et al. · 2020AnimalLYW-6, a novel cryptotanshinone derived STAT3 targeting inhibitor, suppresses colorectal cancer growth and metastasis — medicinal chemistry and in vivo studyView study →Reference 6Chen W et al. · 2010In vitroCryptotanshinone inhibits cancer cell proliferation by suppressing mammalian target of rapamycin-mediated cyclin D1 expression and Rb phosphorylation — in vitro studyView study →Reference 7Pan Y et al. · 2017In vitroCryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer — in vitro studyView study →Reference 8Jeoung NH et al. · 2021In vitroCryptotanshinone prevents the binding of S6K1 to mTOR/Raptor leading to the suppression of mTORC1-S6K1 signaling activity and neoplastic cell transformation — in vitro studyView study →Reference 9Chen W et al. · 2017In vitroCryptotanshinone activates AMPK-TSC2 axis leading to inhibition of mTORC1 signaling in cancer cells — in vitro studyView study →Reference 46Hou Y et al. · 2025In vitroA small molecule cryptotanshinone induces non-enzymatic NQO1-dependent necrosis in cancer cells through the JNK1/2/iron/PARP/calcium pathway — in vitro and in vivo studyView study →}

06Metabolic — AMPK, brown fat, liverShaky24%Coherent AMPK/SIRT1 rodent set; anti-obesity and alcohol-liver models ^{9,49,50Reference 9Chen W et al. · 2017In vitroCryptotanshinone activates AMPK-TSC2 axis leading to inhibition of mTORC1 signaling in cancer cells — in vitro studyView study →Reference 49Ni J et al. · 2024AnimalCryptotanshinone promotes brown fat activity by AMPK activation to inhibit obesity — mouse in vivo studyView study →Reference 50Nagappan A et al. · 2019AnimalCryptotanshinone from the Salvia miltiorrhiza Bunge attenuates ethanol-induced liver injury by activation of AMPK/SIRT1 and Nrf2 signaling pathways — mouse in vivo studyView study →}

07Cardio- & neuroprotectionShaky20%Scattered rodent ischaemia, fibrosis and remodelling models, largely mechanism-first ^{47,51Reference 47Song H et al. · 2023AnimalCryptotanshinone alleviates lipopolysaccharide and cigarette smoke-induced chronic obstructive pulmonary disease in mice via the Keap1/Nrf2 axis — mouse in vivo studyView study →Reference 51Zhang Y et al. · 2019AnimalCryptotanshinone protects against pulmonary fibrosis through inhibiting Smad and STAT3 signaling pathways — mouse in vivo studyView study →}

08AntiplateletShaky18%One rat platelet-aggregation study; the P2Y12 target assignment is docking only ^{35Reference 35Maione F et al. · 2015AnimalMolecular mechanism of tanshinone IIA and cryptotanshinone in platelet anti-aggregating effects: an integrated study of pharmacology and computational analysis — rat platelet and docking studyView study →}

Mechanisms

Two rows are marked proposed deliberately. Both are the most-cited things about this molecule, and both are docking results.

Pharmacokinetics

Absorption is the constraint that bounds every number here.

• Oral bioavailability in rats is 2.1%, against 10.6% intraperitoneally, at a 100 mg/kg dose ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}. Reported plasma concentrations and half-lives across the literature vary by orders of magnitude with route and formulation, which is itself the finding ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}.
• About a fifth of an oral dose becomes tanshinone IIA. Fraction metabolised = 21.0 ± 4.1% in rats ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}; the same biotransformation is documented in pig ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}.
• The extract is not the isolate, pharmacokinetically. Giving rats the liposoluble danshen extract rather than the equivalent dose of pure compound raised the Cmax of cryptotanshinone roughly 8-fold and of tanshinone IIA roughly 10-fold, with correspondingly larger AUCs ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}. A later study confirmed the effect and extended it to tissue distribution — the coexisting constituents particularly promoted entry into lung, heart, kidney, liver and brain ^{28Reference 28Wang D et al. · 2020AnimalComparative pharmacokinetics and tissue distribution of cryptotanshinone, tanshinone IIA, dihydrotanshinone I, and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats — rat pharmacokinetic studyView study →}. A study on the purified molecule systematically understates what the same dose does inside an extract.
• Clearance is CYP-then-UGT. In human liver microsomes cryptotanshinone is converted to six dehydrogenation and hydroxylation metabolites, with CYP2A6, CYP3A4 and CYP2C19 driving hydroxylation and CYP2C19, CYP1A2 and CYP3A4 the dehydrogenation products; glucuronidation then follows via UGT1A9, UGT2B7 and UGT2B4 ^{30Reference 30Zeng J et al. · 2018In vitroCharactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro — in vitro studyView study →}. It is, in the authors’ phrase, extensively metabolised.
• Formulation is the whole development story. Solid lipid nanoparticles, nanocrystals, ethosomes, niosomal hydrogels, cerasomes and self-assembling micelles all exist for this molecule for the same reason — it is a lipophilic solid whose absorption is dissolution-limited, and improving dissolution improves exposure ^{37Reference 37Hu L et al. · 2010AnimalPreparation and enhanced oral bioavailability of cryptotanshinone-loaded solid lipid nanoparticles — rat pharmacokinetic studyView study →}.

Practically: treat in-vitro results above ~10 µM as unreachable systemically; treat the topical and luminal applications (acne, gut inflammation, antibacterial) as the ones absorption does not disqualify; and treat any figure obtained from an extract as belonging to the extract.

Clinical Trials

No trial has administered cryptotanshinone to a human. A PubMed search for cryptotanshinone AND clinical trial[pt] returns two records, and neither is a cryptotanshinone trial: one is a randomised study of a Sanghuang–danshen combination product on arterial stiffness in healthy smokers ^{61Reference 61Lim Y et al. · 2019RCTSynergistic effects of Sanghuang–danshen bioactives on arterial stiffness in a randomized clinical trial of healthy smokers — human trial of a combination productView study →}, the other a mechanistic prostate-cancer paper indexed in error.

ClinicalTrials.gov returns exactly one registered study, NCT01452477 — “Effect of Tanshinone on Hormonal and Metabolic Features in Women With Polycystic Ovary Syndrome,” 100 participants, randomised, quadruple-blind, placebo-controlled, tanshinone 1.0 g three times daily for 12 weeks. It tests a mixed tanshinone preparation, not cryptotanshinone, and its status has been UNKNOWN since 2013 with no results posted ^{18Reference 18Heilongjiang University of Chinese Medic · 2011RCTEffect of tanshinone on hormonal and metabolic features in women with polycystic ovary syndrome (PCOS) — randomised, quadruple-blind, placebo-controlled trial; status UNKNOWN since 2013, no results postedView study →}.

Last checked: August 2026.

Isolate vs. Plant Studies

The split here is unusually clean and unusually one-sided.

All of the pharmacology is isolate. Every mechanism, every rodent model, every MIC and every xenograft here used purified cryptotanshinone. That is a genuine strength — this is a page about a molecule, not about a fraction.

All of the human data is plant, and most of it is a different plant fraction. Dan shen’s clinical evidence base is enormous and it belongs almost entirely to water-soluble products (compound danshen dripping pill) or to a semi-synthetic injectable (tanshinone IIA sodium sulfonate). The nearest human study to this molecule’s own pharmacology — the 30-man LUTS pilot of a Salvia miltiorrhiza extract ^{44Reference 44Kim EY et al. · 2026RCTEfficacy and safety of Salvia miltiorrhiza extract (SAGX) compared with saw palmetto in men with lower urinary tract symptoms: a 12-week, randomized, double-blind, parallel-group pilot study — human trial of a whole extractView study →} — did not report its tanshinone content.

And the two halves are not connected by a bridge. Three things stand between them: absorption (2.1% oral ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}), identity (21% of the dose is tanshinone IIA ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}, and more of it may have oxidised in the stock solution ^{26Reference 26Roth A et al. · 2023In vitroChemical stability and bioactivity of tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone in in vitro test systems — analytical and in vitro studyView study →}), and preparation (a water decoction contains only traces of any tanshinone ^{39Reference 39Pang H et al. · 2016ReviewChemical analysis of the herbal medicine Salviae miltiorrhizae Radix et Rhizoma (danshen) — analytical reviewView study →}).

Prevalence in Nature

Cryptotanshinone is a narrowly distributed molecule. It is a Lamiaceae compound, effectively a Salvia compound, and within Salvia effectively a section-Eusphace root compound. It is not found in culinary sage (cryptotanshinone AND "Salvia officinalis" returns zero PubMed records) or in rosemary, whose diterpene chemistry runs to the phenolic abietanes — carnosic acid and carnosol — rather than the quinones.

Major Natural Sources

Source	Part	Cryptotanshinone	Note
Dan shen (Salvia miltiorrhiza)	root & rhizome	764 ± 71 mg/kg dry wt 38Reference 38Ayvazyan A et al. · 2023Cytotoxic diterpenoids from Salvia glutinosa and comparison with the tanshinone profile of danshen (Salvia miltiorrhiza) — UHPLC-DAD-MS quantificationView study →	The only commercial source; tanshinone IIA measured at 895 mg/kg in the same material
Salvia przewalskii, S. yunnanensis, S. trijuga, S. castanea	root	not individually quantified here	Southwest-Chinese danshen substitutes traded in Chinese herbal markets; tanshinones are their main lipophilic components 29,41Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →Reference 41Kakisawa H et al. · 1968Synthesis of tanshinone-II and cryptotanshinoneView study →
Sticky sage (Salvia glutinosa)	root	6.6–8.3 mg/kg dry wt 38Reference 38Ayvazyan A et al. · 2023Cytotoxic diterpenoids from Salvia glutinosa and comparison with the tanshinone profile of danshen (Salvia miltiorrhiza) — UHPLC-DAD-MS quantificationView study →	The European relative — about 1% of danshen levels; two wild populations sampled
Salvia bowleyana	root	not quantified	Listed among tanshinone-bearing substitute species 29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →

Two structural facts about distribution are worth stating plainly. First, tanshinones are a root chemistry: in a survey of S. miltiorrhiza roots, stems, leaves and flowers across growth stages, the aerial parts contained salvianolic acids, flavonoids and triterpenes, and the liposoluble tanshinones were not detected at all ^{40Reference 40Zeng H et al. · 2017Comparative analysis of the major chemical constituents in Salvia miltiorrhiza roots, stems, leaves and flowers during different growth periods by UPLC-TQ-MS/MS and HPLC-ELSD methods — analytical studyView study →}. Second, total tanshinone content in the root varies roughly five-fold with harvest timing, from about 0.17% to 0.86% of dry weight ^{40Reference 40Zeng H et al. · 2017Comparative analysis of the major chemical constituents in Salvia miltiorrhiza roots, stems, leaves and flowers during different growth periods by UPLC-TQ-MS/MS and HPLC-ELSD methods — analytical studyView study →} — so a “standardised” figure is a snapshot of an agronomic decision as much as a botanical fact.

Discovery & Synthesis

The tanshinone story begins in Tokyo. Nakao and Fukushima published on the chemical composition of the Chinese drug tan-shen in Yakugaku Zasshi in 1934, isolating the first members of the series ^{42Reference 42Nakao M · 1934On the chemical composition of Salvia miltiorrhiza (Chinese drug tan-shen) — the first isolation of the tanshinone seriesView study →}. Cryptotanshinone was reported out of the same Japanese natural-products programme in the following decade; that primary paper is not indexed in PubMed or Crossref, so none is assigned it a date it cannot verify. The name follows the pattern — tanshinone from tan-shen, with crypto- for a constituent that had been hiding in the same fraction.

Its structure was settled by total synthesis in 1968, when Kakisawa, Tateishi and Kusumi published routes to tanshinone-II and cryptotanshinone in Tetrahedron Letters and, in the same year, total syntheses of tanshinone-I, tanshinone-II and cryptotanshinone in Chemical Communications ^{41Reference 41Kakisawa H et al. · 1968Synthesis of tanshinone-II and cryptotanshinoneView study →}; Inouye and colleagues published a parallel set in the Bulletin of the Chemical Society of Japan in 1969.

Manufacture today is entirely extractive — ethanol or supercritical CO₂ from S. miltiorrhiza root — and there is no economic synthetic route. The interesting modern chemistry is in the other direction: cryptotanshinone is used as a scaffold, remodelled into derivatives with better-defined targets. LYW-6 is the clearest example, a structure-based redesign of the parent into a STAT3 binder with a measured Kd ^{5Reference 5Wang H et al. · 2020AnimalLYW-6, a novel cryptotanshinone derived STAT3 targeting inhibitor, suppresses colorectal cancer growth and metastasis — medicinal chemistry and in vivo studyView study →}; DST-3 is a modified cryptotanshinone developed for pulmonary fibrosis, explicitly to improve on the parent’s bioavailability ^{62Reference 62Guan R et al. · 2025DST-3, a novel modified cryptotanshinone, protects against pulmonary fibrosis via inhibiting STAT3/Smad signaling pathway and improves bioavailability — semi-synthetic derivative studyView study →}. Plant-side, tanshinone biosynthesis in S. miltiorrhiza hairy roots and its transcriptional regulation is an active engineering field, with CRISPR and transcription-factor approaches used to raise yields.

Patents: not yet researched.

Toxicity & Safety

Cryptotanshinone carries an unknown flag, and the word is doing precise work. There is no toxicology package for this molecule: no repeat-dose study, no NOAEL, no genotoxicity battery, no reproductive-toxicity dataset, and no human safety data of any kind. A low grading would imply a clean record. What exists is an absent record with two specific flags in it.

The eryptosis finding. Bissinger and colleagues at Tübingen exposed human erythrocytes to cryptotanshinone and found that 10 µM triggered eryptosis — suicidal erythrocyte death, with cell shrinkage, phosphatidylserine externalisation and raised cytosolic Ca²⁺ — and that the effect at 1 µM was abolished by removing extracellular calcium ^{36Reference 36Bissinger R et al. · 2014In vitroStimulation of eryptosis by cryptotanshinone — human erythrocyte in vitro studyView study →}. Their conclusion was that cryptotanshinone is “a powerful stimulator of suicidal erythrocyte death.” These are concentrations at or below those used in most of the anticancer cell work.

The redox chemistry. Cryptotanshinone is an ortho-quinone that generates superoxide in bacterial lysates and inhibits DNA, RNA and protein synthesis non-selectively ^{21Reference 21Lee DS et al. · 1999In vitroAntibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge — in vitro studyView study →}. That is the same chemistry that makes it antibacterial and the same chemistry that makes indiscriminate cytotoxicity the null hypothesis for its cell-line results.

The genotoxicity gap, partly filled by a sibling study. Roth and colleagues tested tanshinone I and tanshinone IIA for cytotoxicity and genotoxicity and found none — but they could not properly test cryptotanshinone and dihydrotanshinone I because those two decomposed in the assay vehicle ^{26Reference 26Roth A et al. · 2023In vitroChemical stability and bioactivity of tanshinone I, tanshinone IIA, cryptotanshinone and dihydrotanshinone in in vitro test systems — analytical and in vitro studyView study →}. So the cleanest genotoxicity data in this class are not about this molecule, and the reason is instability.

Interactions

This is where cryptotanshinone attaches most concretely to dan shen’s headline safety issue, and the attribution needs care in both directions.

The herb-level fact is not in doubt. Salvia miltiorrhiza potentiates warfarin. There are human case reports of raised INR, over-anticoagulation and bleeding ^{33Reference 33Chan TY · 2001Case reportInteraction between warfarin and danshen (Salvia miltiorrhiza) — review of case reportsView study →}, and rat pharmacokinetic/pharmacodynamic work showing danshen alters warfarin’s disposition and prolongs prothrombin time ^{34Reference 34Lo AC et al. · 1992AnimalThe effects of danshen (Salvia miltiorrhiza) on pharmacokinetics and pharmacodynamics of warfarin in rats — rat pharmacokinetic studyView study →}. It is one of the best-documented herb–drug interactions in the materia medica. Anyone on warfarin or another anticoagulant should not take dan shen in any form without medical supervision, and should stop it well before surgery. That warning belongs here whether or not the molecule is implicated.

And here, unusually, part of it does trace to the molecule. Wu and Yeung separated the question by fraction. In rat liver microsomes, the ethyl acetate (tanshinone) extract and the individual tanshinones — tanshinone I, tanshinone IIA and cryptotanshinone — all decreased the formation of 4′-, 6- and 7-hydroxywarfarin, mediated by CYP1A1, CYP2C6 and CYP2C11. The aqueous extract had no effect on warfarin hydroxylation at all. In vivo, danshen decreased warfarin Cmax, prolonged Tmax, reduced hydroxywarfarin formation after 3-day dosing, and raised steady-state plasma warfarin by 23% ^{32Reference 32Wu WW · 2010In vitroInhibition of warfarin hydroxylation by major tanshinones of danshen (Salvia miltiorrhiza) in the rat in vitro and in vivo — rat in vitro and in vivo studyView study →}. So the pharmacokinetic arm of the interaction is a lipophilic-fraction, tanshinone-attributable effect, and cryptotanshinone was one of the three tanshinones tested and found active. This is more than a class warning inherited by default.

Two qualifications keep it honest. The rat CYPs involved (2C6, 2C11) are not human CYP2C9, the enzyme that clears S-warfarin in people, so the human relevance is mechanistic rather than quantitative. And the pharmacodynamic arm — danshen’s own antiplatelet and fibrinolytic activity — is carried mainly by the salvianolic acids, with cryptotanshinone contributing one rat platelet-aggregation study and a docking pose ^{35Reference 35Maione F et al. · 2015AnimalMolecular mechanism of tanshinone IIA and cryptotanshinone in platelet anti-aggregating effects: an integrated study of pharmacology and computational analysis — rat platelet and docking studyView study →}.

Beyond warfarin, three signals sit in the same file:

• CYP3A is affected in an unusual direction. Cryptotanshinone activates CYP3A-mediated midazolam 1-hydroxylation in human liver microsomes in a concentration-dependent manner — heterotropic activation, not inhibition — while tanshinone IIA does the same for testosterone 6β-hydroxylation and cryptotanshinone does not ^{31Reference 31Qiu F et al. · 2010In vitroActivation of CYP3A-mediated testosterone 6β-hydroxylation by tanshinone IIA and midazolam 1-hydroxylation by cryptotanshinone in human liver microsomes — in vitro studyView study →}. Substrate-dependent CYP3A activation is harder to reason about than inhibition and does not permit a simple “avoid CYP3A4 substrates” rule.
• It is itself a CYP and UGT substrate across CYP2A6, 3A4, 2C19, 1A2 and UGT1A9, 2B7, 2B4 ^{30Reference 30Zeng J et al. · 2018In vitroCharactering the metabolism of cryptotanshinone by human P450 enzymes and uridine diphosphate glucuronosyltransferases in vitro — in vitro studyView study →}, so inducers and inhibitors of those enzymes will move its own exposure.
• The extract raises its own exposure ~8-fold relative to the pure compound ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →} — a herb–constituent interaction that makes dose comparisons across preparations unsafe.

Reproductive & Endocrine

Cryptotanshinone’s best-replicated in-vivo effect is suppression of androgen synthesis and androgen-receptor signalling ^{10,11,13,14,16Reference 10Xu D et al. · 2012In vitroCryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells — in vitro and xenograft studyView study →Reference 11Wu CY et al. · 2012In vitroCryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function — in vitro studyView study →Reference 13Yang X et al. · 2011AnimalCryptotanshinone reverses reproductive and metabolic disturbances in prenatally androgenized rats via regulation of ovarian signaling mechanisms and androgen synthesis — rat in vivo studyView study →Reference 14Yu J et al. · 2014AnimalCryptotanshinone reverses reproductive and metabolic disturbances in PCOS model rats via regulating the expression of CYP17 and AR — rat in vivo studyView study →Reference 16Ye D et al. · 2017In vitroCryptotanshinone regulates androgen synthesis through the ERK/c-Fos/CYP17 pathway in porcine granulosa cells — in vitro studyView study →}. In the PCOS models that is the therapeutic intent; in anyone else it is a reason for caution that no study has examined. There is no reproductive-toxicity dataset for the molecule, no developmental study, and no data in pregnancy or lactation. A compound that downregulates CYP17 and antagonises the androgen receptor in rats should not be assumed inert in a developing fetus. Decisions about dan shen intake in pregnancy belong on the dan shen monograph, where the preparation and dose are actually chosen; dan shen itself is traditionally avoided in pregnancy.

Safety at a Glance

❔ Toxicity unknownBleeding risk

• Attribution is clean. 508 of 898 PubMed records name Salvia miltiorrhiza; this is unambiguously a danshen molecule, and effectively only a danshen molecule.
• Anticoagulants. Dan shen potentiates warfarin with human case reports of bleeding, and the pharmacokinetic half of that interaction traces to the tanshinone fraction — cryptotanshinone included — inhibiting warfarin hydroxylation. Do not combine; stop dan shen well before surgery.
• It is an androgen-receptor antagonist and suppresses CYP17. That is the intended effect in the PCOS work and an unstudied liability in anyone else, including in pregnancy.
• No toxicology and no human data. No repeat-dose study, no NOAEL, no genotoxicity battery, no human has taken it under study conditions. Silence is not safety.
• Suicidal erythrocyte death in vitro. 10 µM triggers eryptosis in human red cells via calcium entry, at concentrations at or below those used in the cancer-cell literature.
• Unstable, and it becomes something else. It oxidises to tanshinone IIA in DMSO and in the body (~21% of an oral dose in rats), so neither a research result nor a product label reliably describes what acts.
• CYP3A is activated, not inhibited, and substrate-dependently. An interaction signal that no simple rule covers, and that has never been tested clinically.

Dosage

No human dose of isolated cryptotanshinone exists. Nothing below is a recommendation; these are the exposures research has actually used, given for orientation.

Rodent-to-human scaling is not meaningful here, and the limiting factor is absorption rather than tolerability ^{29Reference 29Zhang Y et al. · 2012ReviewTanshinones: sources, pharmacokinetics and anti-cancer activities — reviewView study →}. Note also that the same nominal dose given as an extract produces roughly eight times the plasma concentration it produces as a pure compound ^{27Reference 27Song M et al. · 2007AnimalEffects of the coexisting diterpenoid tanshinones on the pharmacokinetics of cryptotanshinone and tanshinone IIA in rat — rat pharmacokinetic studyView study →}, so even the animal figures are not interchangeable between preparations.

References

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2. Wu YH, Wu YR, Li B, Yan ZY (2020). Cryptotanshinone: a review of its pharmacology activities and molecular mechanisms — review. Fitoterapia. https://pubmed.ncbi.nlm.nih.gov/32445662/
3. Shin DS, Kim HN, Shin KD, et al. (2009). Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells — in vitro study. Cancer Research. https://pubmed.ncbi.nlm.nih.gov/19118003/
4. Lu L, Zhang S, Li C, et al. (2017). Cryptotanshinone inhibits human glioma cell proliferation in vitro and in vivo through SHP-2-dependent inhibition of STAT3 activation — in vitro and mouse xenograft study. Cell Death & Disease. https://pubmed.ncbi.nlm.nih.gov/28492557/
5. Wang H, Liu Z, Guan L, et al. (2020). LYW-6, a novel cryptotanshinone derived STAT3 targeting inhibitor, suppresses colorectal cancer growth and metastasis — medicinal chemistry and in vivo study. Pharmacological Research. https://pubmed.ncbi.nlm.nih.gov/31982491/
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15. Huang Y, Li W, et al. (2014). Cryptotanshinone reverses ovarian insulin resistance in mice through activation of insulin signaling and the regulation of glucose transporters and hormone synthesizing enzymes — mouse in vivo study. Fertility and Sterility. https://pubmed.ncbi.nlm.nih.gov/24973798/
16. Ye D, Li M, et al. (2017). Cryptotanshinone regulates androgen synthesis through the ERK/c-Fos/CYP17 pathway in porcine granulosa cells — in vitro study. Evidence-Based Complementary and Alternative Medicine. https://pubmed.ncbi.nlm.nih.gov/28167972/
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