Hermetica Superfood Encyclopedia
The Short Answer
Withaferin A is a cytotoxic steroidal lactone derived from Withania somnifera that demonstrates potent anticancer and antiangiogenic properties. This bioactive compound works by inducing apoptosis in cancer cells and inhibiting endothelial cell sprouting with IC50 values as low as 12 nM.
CategoryNamed Bioactive Compounds
GroupCompound
Evidence LevelModerate
Primary Keywordwithaferin A benefits
Synergy Pairings3
Withaferin A (Steroidal Lactone) — botanical close-up
Health Benefits
Origin & History
Natural habitat
Withaferin A is a C28-steroidal lactone naturally isolated from the leaves of Withania somnifera (Ashwagandha) and other plants like Physalis longifolia and Withania coagulans. It is extracted using solvents like ethanol and is commercially available in purified form with >98% purity.
“Withaferin A is a key constituent of Withania somnifera, a cornerstone of Ayurvedic medicine used for centuries as a rejuvenative (rasayana) for stress, vitality, and inflammation. The isolated compound was first identified in 1962 from Indian plant leaves, though traditional use involves whole-plant extracts rather than isolated Withaferin A.”Traditional Medicine
Scientific Research
Current evidence for Withaferin A is primarily preclinical, with no human clinical trials, RCTs, or meta-analyses documented in the research. Studies focus on in vitro and in vivo anticancer properties, including cytotoxicity assays and antiangiogenic effects, but lack PubMed PMIDs for human studies.
Preparation & Dosage
Traditional preparation
No clinically studied dosage ranges for Withaferin A in humans are available. Research uses purified compound (>98% purity) rather than standardized extract doses. Consult a healthcare provider before starting any new supplement.
Nutritional Profile
Withaferin A is a steroidal lactone (withanolide-class phytochemical) isolated primarily from Withania somnifera (ashwagandha), not a conventional macronutrient or micronutrient. It has no meaningful caloric, protein, fat, or carbohydrate contribution at physiologically active doses. Bioactive concentration in ashwagandha root extract: approximately 0.001–0.05% dry weight; in standardized leaf extracts: up to 0.2–1.0% dry weight. Molecular weight: 470.6 g/mol; molecular formula: C28H34O6. Key structural features include an α,β-unsaturated lactone ring and an epoxide group critical for biological activity (covalent binding to target proteins including Hsp90, vimentin, IKKβ). Typical bioactive doses in preclinical studies: 1–10 µM in vitro; 2–10 mg/kg in animal models. Oral bioavailability is limited due to first-pass hepatic metabolism, poor aqueous solubility, and extensive Phase I/II biotransformation; estimated oral bioavailability in rodent models is approximately 20–40%. Co-administration with piperine or lipid-based formulations may enhance absorption. Not a source of vitamins, minerals, or essential fatty acids. Classifies strictly as a bioactive phytochemical/investigational therapeutic compound rather than a nutritional ingredient.
How It Works
Mechanism of Action
Withaferin A induces cytotoxicity in cancer cells through apoptotic pathways, particularly targeting head and neck squamous cell carcinoma lines. The compound demonstrates potent antiangiogenic activity by inhibiting endothelial cell sprouting with an IC50 of 12 nM. Additionally, withaferin A exhibits anti-inflammatory effects through modulation of inflammatory mediator pathways.
Clinical Evidence
Current evidence for withaferin A is limited to preclinical studies, with no completed human clinical trials available. In vitro studies demonstrate cytotoxic effects against specific cancer cell lines including JMAR and MDA-1986 head and neck squamous cell carcinoma models. Endothelial cell sprouting assays show quantified antiangiogenic activity with IC50 values of 12 nM. Human clinical data is needed to establish therapeutic efficacy and safety profiles in cancer patients.
Safety & Interactions
Safety data for withaferin A in humans is limited due to lack of clinical trials. Preclinical studies suggest potential cytotoxic effects that may affect normal cells alongside cancer cells. No established drug interactions or contraindications are documented, though caution is advised with concurrent cancer therapies. Pregnancy and lactation safety has not been established for this compound.
Synergy Stack
Hermetica Formulation Heuristic
Also Known As
(4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergost-2-en-1-oneWFAWithanolide D metaboliteAshwagandha lactoneIndian winter cherry compoundAsgandh active principleSteroidal withanolide
Frequently Asked Questions
What is the IC50 value of withaferin A for antiangiogenic effects?
Withaferin A demonstrates potent antiangiogenic activity with an IC50 of 12 nM in endothelial cell sprouting assays. This indicates strong inhibition of blood vessel formation at very low concentrations.
Which cancer cell lines are sensitive to withaferin A?
Preclinical studies show withaferin A exhibits cytotoxicity against human head and neck squamous cell carcinoma lines, specifically JMAR and MDA-1986 cell lines. These studies demonstrate the compound's selective anticancer properties in laboratory settings.
Has withaferin A been tested in human clinical trials?
No completed human clinical trials for withaferin A are currently available in the literature. All existing evidence comes from preclinical in vitro and animal studies, limiting our understanding of human therapeutic applications.
What is the difference between withaferin A and ashwagandha extract?
Withaferin A is a specific steroidal lactone compound isolated from ashwagandha (Withania somnifera), while ashwagandha extract contains multiple withanolides and other compounds. Withaferin A represents the isolated bioactive component responsible for many of ashwagandha's anticancer properties.
What molecular pathways does withaferin A target?
Withaferin A primarily targets apoptotic pathways in cancer cells and inhibits angiogenic processes in endothelial cells. The compound also modulates inflammatory mediator pathways, though specific receptor targets and enzymatic interactions require further research for complete characterization.
What is the bioavailability of withaferin A when taken as a supplement, and does it need to be taken with food?
Withaferin A is a lipophilic steroidal lactone with limited oral bioavailability, making it more effectively absorbed when consumed with dietary fat. As a naturally occurring compound in ashwagandha root, it is traditionally taken with food or ghee to enhance absorption and cellular uptake. Most preclinical studies demonstrating efficacy used direct cellular exposure rather than oral doses, suggesting that bioavailability remains a limiting factor for systemic effects.
Does withaferin A interact with common medications or chemotherapy drugs?
Withaferin A may potentiate the effects of chemotherapy and immunosuppressive medications due to its ability to inhibit NF-κB signaling and induce cellular stress pathways, though clinical interaction data is limited. It should be used cautiously alongside medications metabolized by cytochrome P450 enzymes, as steroidal compounds can affect enzyme activity. Anyone taking prescription medications, particularly immunosuppressants or anticancer agents, should consult a healthcare provider before supplementing with withaferin A sources.
How strong is the clinical evidence for withaferin A's health benefits in humans compared to preclinical research?
Current evidence for withaferin A is predominantly preclinical, derived from in vitro cell culture and animal studies showing anticancer, anti-inflammatory, and antiangiogenic effects. Human clinical trials specifically testing withaferin A are extremely limited, meaning most efficacy claims remain theoretical rather than proven in humans. The gap between promising laboratory results (such as IC50 values of 12 nM) and real-world human outcomes is substantial, making claims of therapeutic benefit premature without robust randomized controlled trials.
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