15,16-dihydrotanshinone I

Other Names

(-)-1,2-Dihydro-1,6-dimethylphenanthro[1,2-b]furan-10,11-dione(1R)-1,2-dihydro-1,6-dimethyl-phenanthro[1,2-b]furan-10,11-dione(1R)-1,6-dimethyl-1,2-dihydronaphtho[1,2-g][1]benzofuran-10,11-dione(R)-1,6-Dimethyl-1,2-dihydrophenanthro[1,2-b]furan-10,11-dione1,6-Dimethyl-1,2,10,11-tetrahydrophenanthro[1,2-b]furan-10,11-dione1,6-Dimethyl-1,2-dihydrophenanthro[1,2-b]furan-10,11-dione4,17-Dimethyl-15-oxagona-1,3,5(10),6,8,13-hexene-11,12-dioneDHTDHTSDihydrotanshinone IPhenanthro[1,2-b]furan-10,11-dione, 1,2-dihydro-1,6-dimethyl-, (1R)-

Synopsis

15,16-Dihydrotanshinone I

1. Identity and Chemical Characterization

Names and Synonyms

15,16-Dihydrotanshinone I (commonly abbreviated DHTS or DHT) is a naturally occurring phytochemical belonging to the tanshinone family of abietane diterpenoids. Its formal chemical name is (1R)-1,2-dihydro-1,6-dimethyl-phenanthro[1,2-b]furan-10,11-dione. It is also referred to simply as Dihydrotanshinone I and carries the CAS Registry Number 87205-99-0. Its molecular formula is C₁₈H₁₄O₃, with a formula weight of 278.3 g/mol.

Chemical Class and Structure

15,16-Dihydrotanshinone I is a natural abietane diterpenoid that is mainly found in the roots of Salvia miltiorrhiza Bunge (Labiatae). It belongs to a class of lipophilic abietane diterpenoids. Structurally, tanshinones are uniquely characterized by the presence of a 14,16-ether D-ring, with 15,16-dihydrotanshinone representing one of the core members of this structural family. Unlike several related tanshinones, this heterocycle is generally further oxidized to form a furan ring in more oxidized compounds such as tanshinone I and tanshinone IIA. DHTS is a lipophilic, relatively planar, polycyclic quinone molecule. It has limited solubility in DMSO and DMF (approximately 0.2 mg/ml each). In pure form it presents as a crystalline solid.

Natural Source and Abundance in Plant Material

Dihydrotanshinone I is a naturally occurring compound extracted from Salvia miltiorrhiza Bunge, also known as Chinese sage, red sage root, and the Chinese herbal Dan Shen. Salvia miltiorrhiza Bunge, a member of the Lamiaceae family, is valued in traditional Chinese medicine; its dried root (named Danshen) has been used for hundreds of years, primarily for the treatment of cardiovascular and cerebrovascular diseases. DHTS is one of several tanshinones co-occurring in the root; tanshinone derivatives contained in Danshen are composed of approximately 0.29% tanshinone IIA, 0.23% cryptotanshinone, 0.11% tanshinone I, and 0.054% 15,16-dihydrotanshinone I. Phytochemical studies have identified more than 100 compounds from Danshen divided into two categories: hydrophilic ingredients (mainly phenolic acids such as danshensu, salvianolic acids A–I, and rosmarinic acid) and lipophilic ingredients (more than 40 tanshinones, including tanshinone IIA, tanshinone I, cryptotanshinone, and dihydrotanshinone).

Of the tanshinone compounds, cryptotanshinone, dihydrotanshinone I, tanshinone I, and tanshinone IIA have been extensively studied for their anticancer potential; additional Salvia species are known to contain tanshinones, mainly those of the subgenus Glutinaria, of which S. glutinosa is the only species widely occurring in Europe.

Biosynthesis

Tanshinone derivatives are diterpene ortho-quinone compounds. Their biosynthesis proceeds from cryptotanshinone derived from diterpene precursors, with tanshinone derivatives including tanshinone IIA, 15,16-dihydrotanshinone I, and tanshinone I produced through oxidative processes such as demethylation or dehydrogenation of cryptotanshinone. Cryptotanshinone, trijuganone B, and 15,16-dihydrotanshinone I have been identified as chemical markers useful to distinguish Danshen samples processed by different methods.

Preparations and Forms

Historically, the parent plant is administered in several forms. In Chinese traditional medicine there were two primary types of S. miltiorrhiza preparations used by patients: directly prepared herbal raw materials (decoctions, extracts, tinctures) and Chinese patent medicines (water pills, honey pills); however, the use of other products such as injection and ultrafine granular powder is increasing significantly. In experimental settings and as a research-grade material, since tanshinone compounds were first discovered, over 40 related compounds and over 50 hydrophilic compounds have been isolated from Dan Shen. DHTS itself is commercially available as a highly purified isolate (typically ≥98% purity by HPLC) for research purposes and is not currently marketed as a standalone human dietary supplement in most jurisdictions.

2. Traditional and Historical Use

Danshen in Traditional Chinese Medicine

DHTS is a constituent of Danshen (Salvia miltiorrhiza), the herb within which it occurs. The historical and traditional record applies to this parent herb, not to the isolated compound. Salvia miltiorrhiza Bunge was first recorded in the Shennong Bencao Jing (200–300 AD, Han Dynasty), the oldest medicinal monograph in China. The dried root of Salvia miltiorrhiza has been one of the most common traditional herbal medicines for a long time; it is called "Danshen" in China, first documented in the Shennong's Classic of Materia Medica.

Its traditional functions are recorded as HuoXue HuaYu (promote blood circulation and end blood stagnation), YangXue AnShen (nourish the blood and tranquilize the mind), and TiaoJing ZhiTong (regulate menstruation and relieve pain). The root of S. miltiorrhiza has been used as a traditional oriental medicine in the treatment of amenorrhea, coronary heart diseases, angina pectoris, inflammation, and dysmenorrhea.

In the textbooks of academic TCM, S. miltiorrhiza is characterized as a common drug for promoting blood circulation and removing blood stasis. The herb has been officially recorded in the Chinese pharmacopoeia since 1953. It has been used for the treatment of various diseases, such as Alzheimer's disease, diabetes, cerebrovascular disease, coronary heart disease, cancer, hepatocirrhosis, and Parkinson's disease.

Danshen is a famous traditional Chinese herb that has been used clinically for the treatment of various diseases for centuries. The traditional Chinese medicine danshen has long been used for lowering both blood pressure and blood glucose in type 2 diabetes mellitus patients. Red sage (Salvia miltiorrhiza Bunge), also known as Danshen in Chinese, has been used historically and is currently exploited in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM).

It is important to note that within traditional practice, DHTS was never isolated or used as a single chemical entity; rather, it was one component among many in whole-root preparations. The attribution of specific traditional effects to DHTS specifically is a modern scientific inference from fractionation studies.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Chemical Context: The Tanshinone Family

Tanshinones are a class of lipophilic abietane diterpenes rich in Danshen that possess multiple biological effects in vitro and in vivo models. Tanshinones are the main active ingredients in S. miltiorrhiza and exhibit significant pharmacological activities, such as antioxidant activity, anti-inflammatory activity, cardiovascular effects, and antitumor activity. Tanshinones and chemically modified derivatives possess broad cardiovascular and cerebrovascular protective actions; for example, the sodium sulfonate of tanshinone IIA is widely used in the clinic to treat patients with coronary artery disease; their pharmaceutical applications also include antioxidant, antibacterial, anti-inflammatory, antitumor, and anti-HIV activities.

Molecular Targets of DHTS

DHTS has anti-cancer, cardiovascular protective, anti-inflammation, anti-Alzheimer's disease, and other effects; several molecules such as hypoxia-inducible factor (HIF-1α), human antigen R (HuR), and acetylcholinesterase (AChE) have been identified as potential targets for DHTS.

HuR (Human Antigen R) Inhibition

One of the most precisely characterized molecular targets of DHTS is the RNA-binding protein HuR. HuR is a RNA-binding protein that orchestrates the stabilization and translation of mRNAs critical in inflammation and tumor progression, including tumor necrosis factor-alpha (TNF). DHTS was identified through a validated high-throughput screening on a set of anti-inflammatory agents for its ability to prevent HuR:RNA complex formation; it interferes with the association step between HuR and RNA with an equilibrium dissociation constant in the nanomolar range in vitro (Ki = 3.74 ± 1.63 nM). It is a potent inhibitor of the HuR:RNA interaction, active in the low nanomolar range, mainly by limiting the association rate of HuR with RNA. DHTS prevents HuR binding to RNA in a cell-free assay (Ki = 3.74 nM) and inhibits the production of TNF mRNA and protein in MCF-7 cells.

HIF-1α Pathway Modulation

DHTS also modulates hypoxia-inducible factor-1α (HIF-1α) signaling. KEGG pathway analysis revealed downregulated activity of the HIF-1α signaling pathway in endothelioma (EOMA) cells following treatment with DHTS. DHTS treatment caused significant accumulation of polyubiquitinated proteins and HIF-1α, indicating that DHTS might be a proteasome inhibitor that enhances apoptosis caused by the classic ER stress-dependent mechanism. DHTS can reverse metabolic reprogramming in colon cancer cells through a PTEN/AKT/HIF-1α-mediated signaling pathway.

NF-κB Signaling Inhibition

Dihydrotanshinone I was identified as an inhibitor of NF-κB activation; it significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner, and also inhibited TNF-α-induced phosphorylation and degradation of IκBα, and phosphorylation and nuclear translocation of p65. Furthermore, pretreatment of cells with DHTS prevented the TNF-α-induced expression of NF-κB target genes, including anti-apoptosis (cIAP-1 and FLIP), proliferation (COX-2), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, IL-6, and MCP1).

Apoptotic Pathways

DHTS mainly induces intrinsic apoptosis mediated by regulation of Bcl-2 family proteins and activation of caspases, including decreasing mitochondrial membrane potential, inhibiting expression of anti-apoptotic proteins such as Bcl-xL and Bcl-2, increasing pro-apoptotic proteins such as p53, Bax, and Bad, and activating caspase-3/7/8/9. Extrinsic apoptotic pathways are also engaged: treatment with DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, leading to PARP cleavage; DHTS induced sustained JNK phosphorylation and Fas ligand (FasL) expression, and the anti-Fas blocking antibody reversed DHTS-induced cell death.

Endoplasmic Reticulum Stress

DHTS was able to induce ER stress as evidenced by the upregulation of GRP78/Bip and CHOP/GADD153, as well as increases in phosphorylated eIF2α, JNK, and XBP1 mRNA splicing forms in prostate carcinoma cells. DHTS-induced apoptosis was reversed by salubrinal, an ER stress inhibitor, suggesting that DHTS can induce apoptosis of prostate carcinoma cells via induction of ER stress and/or inhibition of proteasome activity.

AMPK/Akt/mTOR and MAPK Signaling

A study investigated the anti-cancer effect of DHTS in terms of cell cycle regulation and the regulation of the AMPK/Akt/mTOR signaling pathway in SK-HEP-1 human hepatocellular carcinoma cells. Treatment with DHTS resulted in increases in the number of cells in the G0/G1 phase, indicating G0/G1 cell cycle arrest in hepatocellular carcinoma cells. DHTS increases AMPKα phosphorylation and acetyl-CoA carboxylase phosphorylation, thus inhibiting TORC2 translocation and thereby promoting glucose uptake.

Acetylcholinesterase Inhibition

Crystal structures of recombinant human acetylcholinesterase in complex with dihydrotanshinone I reveal binding that is specific to only the peripheral site of the enzyme. In mice with scopolamine-induced learning and memory impairment, DHTS (2–4 mg/kg, p.o.) increases latency to step-through in a passive avoidance test approximately 3- to 4-fold, and it inhibits acetylcholinesterase in brain homogenate (IC50 = 25 µM).

Mast Cell Degranulation

DHTS inhibits RHL-2H3 mast cell degranulation with an IC50 value of 14.3 µM and reduces the tyrosine phosphorylation of phospholipase Cγ2 (PLCγ2) and ERK.

Anti-platelet Activity

15,16-Dihydrotanshinone I significantly suppressed collagen-induced liberation of [³H]arachidonic acid from incorporated rabbit platelets, and at 50 µM slightly but significantly inhibited collagen-induced production of thromboxane B2, indicating that DHTS exerts potent anti-platelet activity via suppression of intracellular calcium mobilization and arachidonic acid liberation. It also reduces collagen-induced aggregation of washed rabbit platelets (IC50 = 8.7 µM).

Metabolic and Endocrine Receptor Antagonism

DHTS from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na⁺/K⁺ ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). This dual receptor antagonism provides a proposed mechanistic basis for effects on blood pressure and blood glucose.

Nrf2/HO-1 and Ferroptosis Inhibition

Dihydrotanshinone I can activate Nrf2/HO-1 signal transduction, reduce Fe²⁺, reactive oxygen species (ROS), and MDA levels, and improve mitochondrial function. In vitro investigation showed ferroptosis was reduced by DHTS, as evidenced by a decrease in lipid ROS generation, an increase in GPX4 expression and the ratio of GSH/GSSG, and an improvement in mitochondrial function; the inhibitory effect of DHTS on ferroptosis was decreased after Nrf2 silencing.

Anti-angiogenic and Vascular Effects

DHTS increased the expression of several apoptosis-related proteins, including caspase9, caspase3, PARP, AIF, BAX, cytochrome c, caspase8, and FADD, and significantly inhibited angiogenesis, as indicated by reduced tube formation and diminished expression of vascular endothelial cell growth factor receptor 2 (VEGFR2) and matrix metalloproteinase 9 (MMP-9).

4. Scientific Evidence by Area of Use

Important framing note: The scientific evidence for DHTS is almost entirely preclinical — derived from cell culture (in vitro) and animal (in vivo) models. As of the available literature, no registered clinical trials specifically investigating isolated DHTS in human subjects have been published. All mechanistic findings described below should be understood as hypothesis-generating and not as established clinical efficacy.

4.1 Oncology / Anti-cancer Activity

Breast Cancer

DHTS reduces the viability of MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cells with IC50 values of 0.84, 0.92, and 1.2 µM, respectively. DHTS is a lipophilic compound that has been shown to induce anti-proliferative and apoptotic effects on breast cancer cells. In triple-negative breast cancer (TNBC), DHTS has been shown to induce anti-proliferative and apoptotic effects, and an anti-migratory effect was studied on TNBC cell lines by examining Epithelial Mesenchymal Transition (EMT) changes.

Regarding breast cancer stem cells (CSCs), DHTS inhibits CSC formation, inhibited mammosphere formation in a dose-dependent manner, showed significant tumor growth inhibition in a xenograft model, and reduced the CD44^high/CD24^low- and aldehyde dehydrogenase (ALDH)-expressing cell population and self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44. DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production.

In a metastasis model, DHT more strongly inhibited the growth of breast cancer cells (MDA-MB-231, 4T1, MCF-7, and SKBR-3) than breast epithelial cells (MCF-10a); DHT repressed wound healing, invasion, and migration activities of 4T1 cells; and in the 4T1 spontaneous metastasis model, DHT (20 mg/kg) blocked metastasis progression and distribution in lung tissue by 74.9%. DHT reversed the formation of neutrophil extracellular traps (NETs) induced by phorbol 12-myristate 13-acetate, and ameliorated NETs-induced metastasis.

Evidence strength: These findings are exclusively from in vitro cell line studies and rodent xenograft models. No human clinical trials exist for this specific application.

Acute Myeloid Leukemia (AML)

DHTS is extracted from Salvia miltiorrhiza Bunge, which is a functional food in Asia; it was investigated for its apoptotic effect on the human acute myeloid leukemia (AML) type III HL-60 cell line. Treatment with 1.5 µg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, leading to PARP cleavage and cell apoptosis; DHTS induced sustained JNK phosphorylation and FasL expression; and the JNK-specific inhibitor SP600125 inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a significant effect in attenuating HL-60 tumor growth. In vivo, DHTS at 25 mg/kg per day reduced tumor growth in an HL-60 leukemia mouse xenograft model by 68% relative to control without decreasing body weight.

Evidence strength: Preclinical (in vitro and murine xenograft) only. No human data.

Hepatocellular Carcinoma (HCC)

A published study investigated the anti-cancer effect of DHTS in SK-HEP-1 human hepatocellular carcinoma cells, evaluating anti-proliferative effects by sulforhodamine B assay. Treatment with DHTS markedly resulted in increases in the number of cells in the G0/G1 phase. Regarding AMPK/mTOR signaling, the study investigated the anti-cancer effect of DHTS in terms of cell cycle regulation and regulation of the AMPK/Akt/mTOR signaling pathway in SK-HEP-1 cells. Earlier work demonstrated that DHTS induces apoptosis of HepG2 HCC cells through production of reactive oxygen species and activation of related kinases.

Evidence strength: Preclinical in vitro and in vivo. No human data.

Colorectal Cancer

DHTS is a component of the traditional Chinese medicinal plant Salvia miltiorrhiza; at as low as 2.5 µg/mL concentration it significantly inhibited proliferation of human benign (SW480) and malignant (SW620) colorectal cancer cells, as shown by MTT and flow cytometric analysis. Activating transcription factor (ATF)-3, a basic leucine zipper-type transcription factor, was found to be predominantly up-regulated in DHTS-treated SW480 and SW620 cells; this up-regulation was blocked by a JNK or p38 inhibitor.

Evidence strength: In vitro only. No human data.

Prostate Cancer

DHTS significantly inhibited the proliferation of human prostate DU145 carcinoma cells and induced apoptosis. DHTS was able to induce ER stress as evidenced by the upregulation of GRP78/Bip and CHOP/GADD153, as well as increases in phosphorylated eIF2α, JNK, and XBP1 mRNA splicing forms.

Evidence strength: In vitro only. No human data.

Hemangioma

Fourteen major compounds extracted from Danshen were screened for their ability to inhibit hemangioma cells; of the 14 compounds investigated, DHTS was the most potent modulator of EOMA cell biology. DHTS could significantly decrease EOMA cell proliferation by inducing cell apoptosis, which was much more efficient than propranolol in vitro. In a nude mouse xenograft experiment, DHTS (10 mg/kg) could significantly inhibit the tumor growth of EOMA cells at a dose comparable to propranolol (40 mg/kg).

Mechanistically, DHTS was significantly more effective at inhibiting hemangioma proliferation in vitro and in vivo than the first-line treatment propranolol. KEGG pathway analysis revealed downregulated activity of the HIF-1α signaling pathway in EOMA cells following treatment with DHTS.

Evidence strength: In vitro and murine xenograft models only. No human clinical trials.

4.2 Cardiovascular and Cerebrovascular Protection

Anti-platelet Effects

15,16-Dihydrotanshinone I, as a major component of Danshen, inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization (published in Archives of Pharmacal Research, 2008). This mechanism — suppression of calcium-dependent arachidonic acid release and thromboxane B2 generation — has been characterized in washed rabbit platelet preparations.

Evidence strength: Ex vivo platelet model. No human pharmacodynamic studies are available for this isolated compound.

Ischemic Stroke / Neuroprotection

DHT is a lipophilic tanshinone extracted from Danshen with various pharmacological effects; its specific effect against ischemic stroke was examined using rats with permanent middle cerebral artery occlusion (pMCAO)-induced cerebral ischemia and tert-butyl hydroperoxide-injured PC12 cells. In vitro, ferroptosis was reduced by DHTS as evidenced by decreased lipid ROS generation, increased GPX4 expression and improved GSH/GSSG ratio, and improved mitochondrial function; the inhibitory effect of DHTS on ferroptosis was decreased after Nrf2 silencing; DHTS significantly increased GPX4 expression in the pMCAO model.

Evidence strength: Rodent ischemic stroke model and cell culture. No human clinical data.

Cardioprotection

Tanshinones protect vascular endothelial cells by alleviating oxidative stress and inflammatory damage and regulating NO/ET-1 levels; they also enhance anticoagulant and fibrinolytic capacity and inhibit platelet activation and aggregation. At the level of the parent herb, since 2000, 39 clinical trials have been identified that used S. miltiorrhiza in TCM prescriptions alone or with other herbs for the treatment of patients with cardiovascular disease (CVD). These trials, however, assessed whole-plant preparations rather than isolated DHTS.

Evidence strength for isolated DHTS: Preclinical only. Clinical evidence exists for the parent herb preparation but not for the isolated compound.

4.3 Anti-inflammatory Activity

DHTS was verified to exert an anti-inflammatory effect through TLR4/MyD88/NF-κB/MAPK signaling cascades in lipopolysaccharide-stimulated RAW264.7 macrophage cells. Through HuR inhibition, DHTS suppresses the stabilization of pro-inflammatory mRNAs including TNF-α. DHTS inhibits RHL-2H3 mast cell degranulation and reduces the tyrosine phosphorylation of PLCγ2 and ERK, providing an additional anti-allergic inflammatory mechanism.

Evidence strength: In vitro cell models only. No human clinical evidence for DHTS specifically as an anti-inflammatory agent.

4.4 Metabolic Syndrome, Diabetes, and Blood Pressure

DHTS from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na⁺/K⁺ ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). It was reported that DHTS could elicit therapeutic effects against metabolic syndrome; DHTS increases AMPKα phosphorylation and acetyl-CoA carboxylase phosphorylation, thus inhibiting TORC2 translocation and promoting glucose uptake.

One small clinical trial investigated the broader Danshen extract rather than isolated DHTS: in a double-blind, randomized, placebo-controlled crossover trial in patients with hyperlipidemia and hypertension (N=20), a dose of S. miltiorrhiza root extract 1 g three times daily administered for 28 days did not affect metabolic parameters. This result, however, pertains to a standardized root extract and cannot be attributed specifically to DHTS.

Evidence strength for isolated DHTS: Primarily in vitro mechanistic work. The single small crossover trial assessed the whole extract and returned a negative result for metabolic outcomes; no human trials specific to DHTS exist.

4.5 Alzheimer's Disease and Neuroprotection

Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading acetylcholine in synapses of the nervous system; it is an important target for therapeutic drugs that treat Alzheimer's disease. Crystal structures of recombinant human acetylcholinesterase in complex with dihydrotanshinone I reveal that DHTS binding is specific to only the peripheral site of the enzyme. In mice with scopolamine-induced learning and memory impairment, DHTS (2–4 mg/kg, p.o.) increased latency to step-through in a passive avoidance test by approximately 3- to 4-fold and inhibited acetylcholinesterase in brain homogenate (IC50 = 25 µM).

Evidence strength: Murine behavioral model and structural crystallography. No human clinical data for DHTS in Alzheimer's disease.

4.6 Antibacterial Activity, Including Against Helicobacter pylori

A study assessed the in vitro and in vivo effects of DHTS against standard and clinical H. pylori strains; DHTS demonstrated effective antibacterial activity against H. pylori in vitro (MIC_50/90, 0.25/0.5 µg/mL), with no development of resistance during continuous serial passaging; time-kill curves showed strong time-dependent bactericidal activity for DHTS. Among the tanshinone derivatives, DHTS has also been shown to exhibit moderate antibacterial activity against some Gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus. DHTS possesses strong in vitro antibacterial and antibiofilm activities against various standard and drug-resistant strains of H. pylori; in vivo efficacy studies demonstrated significant clearance of multidrug-resistant H. pylori with inhibited toxicity against normal tissues after dual therapeutic dosing with DHTS and a proton pump inhibitor.

No obvious safety or toxicity signals for DHTS were observed in early toxicity and safety evaluations in that study; DHTS might be a promising lead candidate for the development of anti-H. pylori therapy.

Evidence strength: In vitro minimum inhibitory concentration data and a murine infection model. No human clinical data. This represents one of the more biologically interesting potential applications given the limitation of antibiotic resistance.

5. Body Systems and Health Areas of Association

Oncology: DHTS has shown inhibition of cell proliferation in various cancer cells such as colon, breast, and liver cancers. Additionally, DHT has potent anti-tumor activity against breast, lung, liver, prostate, and ovarian cancer.
Cardiovascular system: Anti-platelet activity, vascular endothelial protection, and inhibition of angiogenesis have been documented in preclinical models. The dried Danshen root has been used for hundreds of years, primarily for the treatment of cardiovascular and cerebrovascular diseases.
Central nervous system: DHTS inhibits acetylcholinesterase and has demonstrated memory-protective effects in scopolamine-impaired rodents, and protects against ischemic stroke-related ferroptosis.
Immune/inflammatory system: Suppression of NF-κB, TLR4/MyD88/MAPK pathways, mast cell degranulation, and HuR-mediated TNF-α stabilization place DHTS among compounds studied for inflammatory modulation.
Metabolic system: Antagonism of mineralocorticoid and glucocorticoid receptors and AMPK activation suggest potential relevance in metabolic syndrome, though clinical validation is absent for the isolated compound.
Gastrointestinal/antibacterial: Demonstrated in vitro and in vivo activity against H. pylori, including drug-resistant strains.
Bone: Red sage has been used historically and is currently exploited in combination with other herbs to treat skeletal diseases in traditional Chinese medicine.

6. Dosages Reported in Preclinical Studies

No human clinical dosing guidelines exist for isolated DHTS. The following dosages are those reported in specific peer-reviewed preclinical studies and are presented solely as documented experimental parameters, not as recommended human doses:

Rodent xenograft (leukemia model): DHTS at 25 mg/kg per day reduced tumor growth in an HL-60 leukemia mouse xenograft model by 68% without decreasing body weight.
Rodent hemangioma xenograft: In a nude mouse xenograft experiment, DHTS at 10 mg/kg could significantly inhibit the tumor growth of EOMA cells, comparable to propranolol at 40 mg/kg.
Rodent scopolamine memory model (oral): DHTS at 2–4 mg/kg administered orally increased step-through latency approximately 3- to 4-fold in scopolamine-induced memory-impaired mice.
Rodent breast cancer metastasis model: In the 4T1 spontaneous metastasis model, DHTS at 20 mg/kg blocked lung metastasis progression by 74.9%.
In vitro anti-cancer (breast cancer): IC50 values against MCF-7, MDA-MB-231, and SK-BR-3 cells were 0.84, 0.92, and 1.2 µM, respectively.
In vitro colorectal cancer: DHTS at as low as 2.5 µg/mL significantly inhibited proliferation of SW480 and SW620 colorectal cancer cells.
In vitro leukemia: Treatment with 1.5 µg/mL DHTS activated apoptotic machinery in HL-60 cells.
In vitro mast cell inhibition: IC50 of 14.3 µM for mast cell degranulation inhibition.
In vitro anti-platelet: IC50 of 8.7 µM for collagen-induced rabbit platelet aggregation.
In vitro acetylcholinesterase inhibition: IC50 of 25 µM in brain homogenate.
In vitro antibacterial (H. pylori): MIC50/90 against H. pylori of 0.25/0.5 µg/mL.
In vitro HuR inhibition: Equilibrium dissociation constant Ki = 3.74 ± 1.63 nM for HuR:RNA complex disruption.

Regarding the parent herb in a human study, a dose of S. miltiorrhiza root extract 1 g three times daily for 28 days was used in a small clinical crossover trial, though again this applies to the complex extract, not isolated DHTS.

7. Safety Considerations and Interactions

Preclinical Toxicology

In early toxicity and safety evaluations conducted in the context of anti-H. pylori research, no obvious safety or toxicity signals for DHTS were observed; the authors noted it might be a promising lead candidate for development. In the HL-60 xenograft study, DHTS at 25 mg/kg per day reduced tumor growth without decreasing body weight in the treated animals, suggesting an absence of overt systemic toxicity at that dose in the model, though comprehensive toxicological profiling data have not been published in the accessible literature.

Lipophilicity and Solubility Limitations

DHTS has limited aqueous solubility, with values of approximately 0.2 mg/mL in both DMSO and DMF, indicating poor water solubility. This presents formulation challenges and means that systemic bioavailability from oral preparations requires careful pharmaceutical consideration. This is a significant constraint for any future human use and is a recognized limitation in DHTS drug development.

Mineralocorticoid and Glucocorticoid Receptor Antagonism

DHTS potently antagonized both mineralocorticoid and glucocorticoid receptors and efficiently inhibited the expression of their target genes including Na⁺/K⁺ ATPase, G6Pase, and PEPCK. This broad receptor antagonism profile implies potential for clinically relevant interactions affecting fluid and electrolyte balance, blood glucose regulation, and adrenocortical hormone action. Individuals on corticosteroid therapy, mineralocorticoid antagonists, or with adrenal insufficiency could theoretically be affected, though no clinical studies have confirmed this in humans.

Potential for Anti-coagulant Interactions

Given its anti-platelet activity — potent anti-platelet activity via suppression of intracellular calcium mobilization and arachidonic acid liberation — DHTS, if consumed as part of Danshen preparations, could theoretically potentiate the effects of anticoagulant and antiplatelet drugs. This concern is well-documented for the parent herb: Danshen-containing preparations have known pharmacokinetic interactions with warfarin in clinical practice, attributed to shared CYP enzyme metabolism, though this pharmacokinetic interaction data derives from the parent herb and whole-extract studies.

Anti-estrogenic / Endocrine Considerations

Tanshinones as a class, including DHTS, have been investigated for interactions with sex hormone receptors. Dihydrotanshinone (DHTS) is a component of the well-known traditional Chinese medicinal plant Salvia miltiorrhiza and is used to treat cardiovascular disease, hepatitis, inflammation, and cancer. As DHTS acts on both mineralocorticoid and glucocorticoid receptor pathways, and given structural similarities within the abietane diterpene class, its interaction with steroid hormone receptors more broadly warrants monitoring in any future clinical development.

Absence of Human Safety Data

No dedicated Phase I human safety, tolerability, or dose-escalation studies for isolated DHTS have been identified in the published literature. All safety inferences currently derive from preclinical models and from clinical experience with whole Danshen preparations. The gap between preclinical observations and validated human safety data is substantial and represents a principal limitation of the current evidence base.

Evidence Maturity Summary

The preponderance of research on DHTS is in vitro or in animal models, published predominantly between 2000 and 2025. Among tanshinone compounds, 15,16-dihydrotanshinone I has received much attention in recent years; a systematic review carefully selected, analyzed, and summarized high-quality publications related to its pharmacological effects and underlying mechanisms. Despite this growing body of preclinical literature, translation to human clinical endpoints has not yet occurred for the isolated compound.

References

Health Conditions

Health conditions that 15,16-dihydrotanshinone I may help support.

No conditions available.

Body Systems

Body systems that 15,16-dihydrotanshinone I may help support.

No body systems available.