IngredientsSotetsuflavone is a naturally occurring biflavonoid — a member of the broader polyphenol family in which two flavonoid (specifically flavone) units are covalently linked. Biflavonoids are polyphenol compounds comprising two identical or non-identical flavonoid units joined in a symmetrical or unsymmetrical manner through an alkyl or an alkoxy-based linker of varying length. Within the biflavonoid subclass, sotetsuflavone belongs to the amentoflavone series. 7′′-O-methylamentoflavone (sotetsuflavone) is a natural derivative of amentoflavone with a single methoxyl group. That is, sotetsuflavone is structurally identical to amentoflavone except for the addition of a methoxy substituent at the 7′′ position.
Sotetsuflavone's molecular formula is C31H20O10, containing five hydroxyl groups and one methoxyl group, and it was found to be a monodemethylated compound of ginkgetin. This flavone has been named sotetsuflavone. Its CAS registry number is 2608-21-1, and its molecular weight is approximately 552.49 g/mol. Yellow microcrystals with a melting point of 263–264°C (decomp.) were originally obtained from the dried leaves of Cycas revoluta Thunb. (Cycadales).
Sotetsuflavone is closely related to a family of amentoflavone-type biflavonoids. The natural derivatives with a single methoxyl group include 7-O-methylamentoflavone (sequoiaflavone), 4′-O-methylamentoflavone (bilobetin), 7′′-O-methylamentoflavone (sotetsuflavone), and 4′′′-O-methylamentoflavone (podocarpusflavone A). Sotetsuflavone can therefore be regarded as a monomethyl ether derivative of amentoflavone, differing from ginkgetin by the loss of one methoxy group.
In research settings, sotetsuflavone is isolated as a pure compound and characterized by HPLC-DAD, HPLC-ELSD, mass spectrometry, and 1D/2D NMR spectroscopy. Identification and structural elucidation of isolated biflavonoids, including sotetsuflavone, are based on spectral data analysis including 1D and 2D NMR. No standardized commercial dietary supplement preparations have been formally registered or pharmacopoeially monographed for sotetsuflavone as a standalone ingredient; it is available from phytochemical research suppliers as a reference standard at ≥95% purity for scientific purposes only.
Sotetsuflavone takes its name from sotetsu, the Japanese name for Cycas revoluta. Cycas revoluta (sotetsu [Japanese: ソテツ], sago cycad, sago palm, king sago, Japanese sago palm) is a species of gymnosperm in the family Cycadaceae, native to southern Japan including the Ryukyu Islands. Sotetsuflavone is a flavonoid compound isolated from Cycas revoluta Thunb. It has also been isolated from other Cycas species: the secondary metabolites ginkgetin and sotetsuflavone have been isolated from Cycas media R.Br dichloromethane fraction. Furthermore, sotetsuflavone occurs in the genus Cycas thouarsii R.Br. Sotetsuflavone (SF) is an antioxidant flavonoid derived from the Cycas thouarsii R.Br. plant.
Sotetsuflavone is not exclusive to the cycad family. From the autumn leaves of Metasequoia glyptostroboides have been isolated the biflavonyls hinokiflavone, isocryptomerin, amentoflavone, sotetsuflavone, amentoflavone-7″,4‴-dimethylether, sciadopitysin, and several hitherto unknown dihydrobiflavonyls, as well as the flavone apigenin. It has also been found in Amentotaxus yunnanensis and Torreya yunnanensis of the family Taxaceae: the known isolates from A. yunnanensis have been identified as sequoiaflavone, sotetsuflavone, 7,7′′-dimethoxyamentoflavone, lutein, β-sitosterol, and sequoyitol. The occurrence of the biflavonoid sotetsuflavone in both A. yunnanensis and T. yunnanensis suggests that these two genera are closely related.
From a broader phytochemical perspective, the leaves of cycad plants are notably rich in flavonoids, including sotetsuflavone, amentoflavone, and bilobetin. Cycads contain generally non-toxic compounds; cycad biflavonoids and triterpenoids feature most prominently in chemical listings, alongside other phenolic compounds, carbohydrates, steroidal compounds, carotenoids, fatty acids, leaf waxes, and cone volatiles.
Cycas revoluta Thunb. (sago palm), a cycad native to southern Japan, is widely cultivated and has a long history of ethnobotanical use, including as a famine food and in traditional medicine, but is also well known for its pronounced toxicity to humans and animals. Ancient records report that Cycas revoluta is sweet, flat, astringent, and slightly toxic, with fever-reducing and coagulant abilities, and was used for dispersing congestion. Some Chinese medicines, including Cycas revoluta Thunb., have demonstrated chemosensitization effects, which provides novel insights for anti-cancer treatments.
Cycas revoluta is an ornamental plant which has had some of its parts used in treating some forms of cancers, relieving headaches, giddiness, and sore throat. Historical use of the plant for medicinal purposes was centered in Japanese and Chinese traditions and focused on the leaves and seeds, though these must be distinguished from the isolated biflavonoid sotetsuflavone itself, which was not identified until modern phytochemical analysis.
In ancient times, the plant's pith was processed to create a starch known as sago, though this required careful preparation to remove toxins. Although Cycas revoluta has been utilized in various traditional contexts, the plant is highly toxic and cannot be consumed directly without proper processing. The historical use of its starch, sago, was labor-intensive due to the need to wash out the toxins.
It must be emphasized that the traditional use of Cycas revoluta relates to whole-plant preparations or processed plant parts, not to isolated sotetsuflavone. Sotetsuflavone as a discrete compound has been characterized only through modern analytical chemistry. No documented traditional system of medicine is known to have specifically identified or employed isolated sotetsuflavone. Many medicinal properties and traditional uses of plants are attributed to the presence of biflavonoids among their secondary metabolites, but attributing specific traditional use to sotetsuflavone per se would be anachronistic.
Sotetsuflavone is a biflavone composed of two apigenin-type units. Structurally, biflavonoids are polyphenol compounds comprising two identical or non-identical flavonoid units joined in a symmetrical or unsymmetrical manner through an alkyl or an alkoxy-based linker of varying length. In sotetsuflavone, the two flavone rings are connected through a C–C linkage, and a single methoxy group at the 7′′ position distinguishes it from the unmethylated parent amentoflavone. Sotetsuflavone, linked via C8–C3‴, inhibits dengue virus RNA-dependent RNA polymerase (RdRp) more effectively than related biflavonoids.
Multiple preclinical studies have identified mechanistic pathways through which sotetsuflavone exerts its biological effects on cancer cells:
Through up-regulating SOCS3, sotetsuflavone altered the PI3K/Akt pathway, mitigating oxidative stress, blocking the outflow of inflammatory mediators, and impeding gastric ulcer development. Overall, sotetsuflavone, by SOCS3-mediated JAK2/STAT3 suppression, might considerably reduce oxidative stress, inflammation, and ulceration caused by indomethacin in the stomach.
Evidence level: Preclinical only (in vitro and in vivo animal models). No human clinical trials reported.
The most extensively investigated area for sotetsuflavone is its activity against lung cancer cell lines. Sotetsuflavone is isolated from Cycas revoluta Thunb. and has biological activity against tumors; however, the anti-proliferative effects of sotetsuflavone on A549 cells and its mechanism were not fully elucidated until recent investigation. Studies investigated the mechanisms of growth inhibition, cell cycle arrest, and apoptosis in non-small cell lung cancer A549 cells induced by sotetsuflavone, and evaluated whether sotetsuflavone can be safely utilized by humans as a therapeutic agent.
Key findings from these in vitro studies include: sotetsuflavone had significant antiproliferative activity against A549 cells; the ROS content increased while the mitochondrial membrane potential and the ratio of Bcl-2/Bax decreased; and sotetsuflavone could effectively inhibit G0/G1 cycle progression and then induce the endogenous apoptosis pathway. Sotetsuflavone had an inhibitory effect on A549 cells and causes apoptosis of A549 lung cancer cells, and may be a novel candidate for anti-tumor therapy in patients with lung cancer.
On the question of metastasis, one in vitro study published in Cell Death Discovery (2018) established that sotetsuflavone suppresses invasion and metastasis in non-small-cell lung cancer A549 cells by reversing EMT via the TNF-α/NF-κB and PI3K/AKT signaling pathway.
Regarding autophagy, researchers determined that sotetsuflavone induces autophagy in NSCLC cells through its effects upon blocking of the PI3K/Akt/mTOR signaling pathways, and that this study may provide a theoretical basis for future clinical applications.
Sotetsuflavone has demonstrated notable anti-tumor efficacy, presenting a promising candidate for the development of novel therapeutics for non-small cell lung cancer (NSCLC). All evidence at this point is from cell culture (in vitro) and animal model experiments; no human trials exist.
Evidence level: Preclinical only (in vitro cell culture). No human clinical trials reported.
Research has explored whether Cycas revoluta extract (which contains sotetsuflavone) can overcome drug resistance in gastric cancer cells. The natural extract of Cycas revoluta Thunb. effectively inhibits gastric cancer cell growth, migration, and invasion, and can be used in combination with 5-Fu to enhance its anti-cancer effects through the AKT-mTOR pathway. These studies used plant extract containing sotetsuflavone rather than pure isolated sotetsuflavone, which is an important methodological limitation.
Evidence level: Computational/in silico only. No cell-line or animal data published; no human trials.
A study incorporated network pharmacology, single gene survival analysis, gene expression analysis, and molecular docking to reveal the mechanism of sotetsuflavone in the treatment of pancreatic cancer. It acquired 31 hub targets for the treatment of pancreatic cancer by sotetsuflavone, including ABCB1, AURKA, CDK1, and others. Kaplan-Meier survival analyses demonstrated that ABCB1, AURKA, CDK1, HDAC6, MET, and MMP3 are promising hub targets that can be used as biomarkers for pancreatic cancer diagnosis and prognosis. This represents a hypothesis-generating computational study and does not constitute experimental validation.
Evidence level: In vitro enzyme inhibition assay only. No animal or human data.
Sotetsuflavone has been rigorously characterized as an inhibitor of the dengue virus NS5 RNA-dependent RNA polymerase (RdRp) in biochemical assays. A 2013 structure-activity relationship (SAR) study published in Planta Medica (Coulerie et al., PMID 23929244) tested 23 biflavonoid compounds from Dacrydium spp. against the DENV-NS5 RdRp. Sotetsuflavone, with an IC50 = 0.16 µM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature. The study concluded that the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and the degree of oxygenation of flavonoid monomers influences their antidengue potential.
This activity is of interest given that, as noted by the researchers, dengue virus is the world's most prevalent human pathogenic arbovirus, and there is currently no established specific treatment. Nevertheless, the enzyme-inhibition IC50 was measured in a cell-free biochemical assay only; antiviral activity in cell culture or in vivo has not been published for isolated sotetsuflavone.
Sotetsuflavone is also noted in one review of plant-based antivirals as a compound that showed inhibition of important viral replication enzymes: emodin, baicalin, cryptotanshinone, silvestrol, sotetsuflavone, and iguesterin showed inhibition of important viral replication enzymes.
Evidence level: In vitro and in vivo (animal model) for E. faecalis; in silico docking. No human trials.
A study published in Antibiotics (2022, PMID 35906004) investigated ginkgetin and sotetsuflavone, both isolated from Cycas media R.Br., against Enterococcus faecalis. The antibacterial and antivirulence activities of the isolated compounds were investigated using docking studies and in vitro by determination of the minimum inhibitory concentrations (MICs). Flow cytometry and scanning electron microscopy (SEM) were utilized to assess the effect of sotetsuflavone on the tested bacteria. Crystal violet assay and qRT-PCR were used to test the effect on biofilm-forming ability of E. faecalis isolates. In addition, a systemic infection model was utilized in vivo to investigate the antibacterial activity. In addition to its growth inhibition ability, sotetsuflavone showed potent antivirulence activity, revealing notable anti-biofilm activity, and significantly downregulated the inflammatory cytokines IL-1β, IL-6, and TNF-α.
Evidence level: In vivo animal model (rat) combined with network pharmacology. No human clinical data.
A 2025 study published in the Journal of Nutritional Biochemistry (El Tabaa et al.) investigated sotetsuflavone's gastroprotective potential. The study aimed to explore the effectiveness of sotetsuflavone against indomethacin-induced gastric ulcers, using network analysis and molecular docking to identify the specific targets and pathways related to sotetsuflavone and stomach ulcers, and validated the in vivo pharmacological action of sotetsuflavone with 36 rats divided into six groups. Through up-regulating SOCS3, sotetsuflavone altered the PI3K/Akt pathway, mitigating oxidative stress, blocking the outflow of inflammatory mediators, and impeding gastric ulcer development. Overall, sotetsuflavone, by SOCS3-mediated JAK2/STAT3 suppression, might considerably reduce oxidative stress, inflammation, and ulceration caused by indomethacin in the stomach.
Evidence level: In vivo animal model only.
Prior investigation into the activity of total flavonoids from Cycas revoluta Thunb. in vivo found that these flavonoids can regulate the expression of interleukin-2 and interleukin-10 in immune cells and inhibit the growth and metastasis of tumor cells in a Lewis lung cancer mouse model. This line of work concerns the total flavonoid fraction of the plant rather than isolated sotetsuflavone, and species-to-species translation of results is uncertain.
No human clinical dosage data exist for sotetsuflavone. The following dosages are reported exclusively from preclinical research and are not applicable to human supplementation:
Key gaps in the literature include inadequate extract standardization, limited bioavailability and safety data, and overreliance on single-study findings. No established therapeutic dose in humans can be cited from the peer-reviewed literature.
The source organisms for sotetsuflavone present significant toxicological concerns that must be distinguished from the profile of the isolated compound itself. Cycas revoluta is toxic to humans and pets, with all parts of this plant toxic and containing a substance called cycasin. The seeds are particularly dangerous. Beyond flavonoids, cycads are a source of distinctive bioactive compounds, namely azoxy compounds, sterols, and non-protein amino acids. Certain cycad-derived constituents, such as β-N-methylamino-L-alanine (BMAA), β-N-oxalylamino-L-alanine (BOAA), methylazoxymethanol (MAM), cycasin, β-sitosterol, and β-D-glucoside, have been associated with neuropathological conditions like amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC).
It is vital to raise awareness among researchers of the potential toxicity associated with the medicinal use of cycad seeds and roots. As new compounds continue to be isolated and purified from cycads, there is a need to integrate and summarize the details of these compounds.
Studies investigated the mechanisms of growth inhibition, cell cycle arrest, and apoptosis in non-small cell lung cancer A549 cells induced by sotetsuflavone, and also evaluated whether sotetsuflavone can be safely utilized by humans as a therapeutic agent. However, no clinical pharmacokinetic, toxicokinetic, or formal human safety studies of isolated sotetsuflavone have been published in the available literature.
Key gaps include inadequate extract standardization, limited bioavailability and safety data, and overreliance on single-study findings. Any assessment of medicinal prospects must be grounded in a critical appraisal of evidence quality, reproducibility, and safety rather than a descriptive accumulation of reported activities.
The notoriety of cycad-derived toxicity, notably within the context of Guam's neurological disease cluster, has precipitated an established emphasis on toxicological research in this field. This historical episode — in which populations consuming cycad-derived food developed a high-incidence neurodegenerative syndrome — underscores the need to carefully distinguish between toxins present in crude plant preparations and the pharmacological profile of a single purified biflavonoid extracted therefrom.
Ethnobotanical, chemical, and clinical research relating to the methylazoxymethanol (MAM) glycosides and the compound β-N-methylamino-L-alanine (BMAA) are commonly implicated in human and animal cycad toxicity. Sotetsuflavone is chemically unrelated to cycasin, MAM, or BMAA; it is a polyphenolic biflavonoid, and the available toxicological literature does not attribute the cycad neurotoxic syndrome to biflavonoids.
No documented drug-drug or herb-drug interaction data for isolated sotetsuflavone are available in the peer-reviewed literature. No pharmacokinetic data (absorption, distribution, metabolism, or excretion) for sotetsuflavone in humans or animals have been published in accessible sources. The absence of such data is itself a critical evidence gap: despite the prevalent focus on crude extracts and total flavonoid content, our understanding of the nuanced pharmacodynamics of cycads lags considerably behind.
Particular emphasis must be placed on distinguishing traditional knowledge from experimentally validated findings, separating in vitro observations from in vivo relevance, and explicitly weighing reported pharmacological activities against documented toxic risks.
The current state of sotetsuflavone research is summarized as follows:
Health conditions that Sotetsuflavone may help support.
Body systems that Sotetsuflavone may help support.
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