IngredientsShikonin is a naturally occurring naphthoquinone found in the dried root of the plant Lithospermum erythrorhizon. This perennial herbaceous plant is native to East Asia, including Japan, Korea, and China, and is commonly known by various names such as gromwell, purple gromwell, or "Zicao" in Chinese. The dried root of L. erythrorhizon, known as zicao or purple gromwell and referred to as shikon in Japanese, is a commonly used traditional Chinese herbal medicine in China and Taiwan.
Shikonin and its derivatives are the red pigments extracted from the roots of the Boraginaceae family, which includes different genera such as Arnebia, Alkanna, Anchusa, Echium, Lithospermum, and Onosma. A small number of medicinal plants found in the northwestern Himalayas also produce shikonin in the roots. Other named species in the Boraginaceae family that contain shikonin derivatives include Echium lycoris, Arnebia euchroma (Royle) Johnst., Onosma armeniacum K., Eritrichium sericeum Lehm., Arnebia decumbens, Arnebia hispidissima, Lithospermum canescens (Michx.) Lehm., and Alkanna tinctoria (L.) Tausch.
The successful production of shikonin derivatives on a large scale from the cell, tissue, and hairy root (transgenic root) cultures of L. erythrorhizon has been achieved.
The IUPAC name of shikonin (C16H16O5) is 5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-1,4-naphthoquinone, determined by Brockmann and Liebigs in 1936, who further determined the enantiomer of shikonin, named alkannin. The shikonin (R-enantiomer) exists as an enantiomeric pair with alkannin (S-enantiomer), hence known as A/S, and shows various pharmacological activities. The racemic mixture of the two is known as shikalkin.
Shikonin is a derivative of 1,4-naphthoquinone, biosynthesized from two precursors, geranyl diphosphate (GPP), via the mevalonate pathway, and p-hydroxybenzoic acid (PHB), via the phenylpropanoid pathway.
Shikonin is a naturally occurring bioactive compound, a naphthoquinone pigment, responsible for the deep red or purple color found in the roots of certain plants. These two red pigments — shikonin and its enantiomer alkannin — have traditionally been used as natural colorants in textile, food, and cosmetic industries.
After isolation and purification from L. erythrorhizon, five shikonin derivatives were isolated: shikonin, deoxyshikonin, acetylshikonin, β-hydroxyisovalerylshikonin, and isobutyrylshikonin. The most abundant compounds in the root are acetylshikonin (44.6%) and β-hydroxyisovalerylshikonin (26.8%). Broader extraction of Echium italicum roots has yielded additional pigments including propionylshikonin, tiglylshikonin, 3,3-dimethylacrylshikonin, angelylshikonin, 2-methyl-n-butyrylshikonin, and isovalerylshikonin. Approximately 35 derivatives of alkannin and shikonin have been isolated from various plants of the Boraginaceae family and extensively investigated for a wide range of biological activities.
The heat and light stability of these compounds was studied, and it was found that the more photodegraded or thermally degraded a compound is, the more unstable it becomes. Based on half-life, deoxyshikonin and isobutyrylshikonin were the most thermally unstable compared to other derivatives; however, in light, all five shikonin derivatives possessed a similar half-life, indicating almost similar stability.
Due to its high lipophilicity, shikonin is generally used in creams and ointments, that is, oil-based preparations; indeed, its insolubility in water is usually the cause of its low bioavailability. Pharmaceutical innovation of shikonin with novel drug delivery systems such as nanoparticles, liposomes, microemulsions, nanogel, cyclodextrin complexes, micelles, and polymers is beneficial to the development of shikonin-based drugs. To address limitations related to solubility and bioavailability, novel formulations such as nanoparticles, liposomes, and derivatives like β,β-dimethylacrylshikonin have been developed, showing improved pharmacological profiles and reduced toxicity in experimental models.
The shikonin-containing root has a long history of use, particularly in Traditional Chinese Medicine (TCM), spanning over 2,000 years. Lithospermum erythrorhizon, also known as lithospermum paste, was first recorded in the classic Chinese medical book Shennong's Herbal Classic. Since ancient times, it has been widely used to reduce body surface heat, promote blood circulation, clear congestion, and detoxify. Medicinal use of the root of Lithospermum erythrorhizon dates back to the second century, but the first written reference to its therapeutic qualities can be found in a traditional Chinese medical text from 1596, Pen Ts'ao Kang Mu.
In TCM, it was traditionally used to "clear heat" and "cool the blood," addressing conditions like skin inflammation, rashes, burns, and external wounds. It has been used for thousands of years for treatment of macular eruptions, measles, smallpox, eczema, carbuncles, and burns. Shikonin has the pharmacological effect of promoting wound healing when used as a topical treatment in traditional Chinese medicine: its effect on skin repair is particularly prominent, and it is often made into a paste or infused oil.
Lithospermum erythrorhizon, a traditional Chinese medicine, is known for its sweet, salty, and cooling taste. It primarily regulates the heart and liver meridians, offering various benefits such as bringing down heat, cooling the blood, detoxifying, and minimizing rashes.
From ancient times, Lithospermum erythrorhizon extract or shikonin has been extensively used to treat ulcers, wounds, and burns. Further, shikonin-based pharmaceutical formulations with wound-healing potential have been on the market for a considerable time.
Shikonin is a natural dye that has been used for several centuries for coloring clothes, as a food pigment, and as traditional Chinese medicine. It is a bioactive compound with potential applications in the food, cosmetics, textile, and pharmaceutical industries. L. erythrorhizon has been used traditionally as medicine in China, and as a dye for staining fabrics and food colorants; it has been cultivated in China, Korea, and other Asian countries.
Alkannin, the S-enantiomer of shikonin, is a natural dye obtained from the extracts of Alkanna tinctoria, which is found in the Mediterranean region. The dye is used as a food coloring and in cosmetics; within the European E number schedule, it is numbered E103.
Shikonin was first isolated as its acetate from the roots of L. erythrorhizon by the Japanese chemists Majima and Kuroda in 1922. The chemical structure as a naphthoquinone derivative was first determined by Hans Brockmann in 1936. Because of its physical and chemical similarities to naphthazarin, Kuroda and Majima's original description of shikonin's structure was inaccurate, and Brockmann later correctly revised the structure.
The naphthoquinone shikonin is the main active principle of Zicao, a traditional Chinese herbal medicine made from the dried root of Lithospermum erythrorhizon. Studies carried out over the past 30 years have demonstrated that many of the effects historically associated with the use of this root have a scientific basis, with shikonin and its derivatives being responsible for its pharmacological properties.
Shikonin is a derivative of 1,4-naphthoquinone, biosynthesized from two precursors: geranyl diphosphate (GPP), via the mevalonate pathway, and p-hydroxybenzoic acid (PHB), via the phenylpropanoid pathway. The chiral pairs alkannin/shikonin are mainly obtained from the roots of around one hundred and fifty species belonging to Lithospermum, Alkanna, Onosma, Echium, Cynoglossum, and Anchusa of the family Boraginaceae. It was observed that both alkannin and shikonin are synthesized simultaneously during biogenesis in the identical plant.
Shikonin exerts multiple therapeutic efficacies mainly by regulating the NF-κB, PI3K/Akt/MAPKs, Akt/mTOR, TGF-β, GSK3β, and TLR4/Akt signaling pathways, the NLRP3 inflammasome, reactive oxygen stress, and Bax/Bcl-2.
Anticancer mechanisms: Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and kinase-mediated signalling. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It also disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect.
PKM2 inhibition and the Warburg effect: Shikonin, a naphthoquinone isolated from Lithospermum, inhibits tumor aerobic glycolysis and tumor growth. It dose-dependently inhibited glucose uptake and lactate production in Lewis lung carcinoma (LLC) and B16 melanoma cells, confirming the inhibitory effect of shikonin on tumor aerobic glycolysis. Treatment with shikonin also decreased tumor cell ATP production. Furthermore, a PKM2 inhibitor or activator respectively altered the effect of shikonin on tumor cell aerobic glycolysis, suggesting that suppression of cell aerobic glycolysis by shikonin occurs through decreasing PKM2 activity.
Necroptosis induction: Death receptor-mediated apoptosis can be diverted to necroptosis when apoptosis signaling is blocked. Shikonin-induced necroptosis can be reverted to apoptosis in the presence of necrostatin-1 (Nec-1), a specific necroptosis inhibitor, and this death mode switch is at least partially due to the conversion from mitochondrial inner membrane permeability to mitochondrial outer membrane permeability, associated with Bax translocation.
Anti-inflammatory mechanisms: Shikonin alleviates chronic inflammation at the wound site by inhibiting the nuclear factor-κB (NF-κB) pathway. Accumulated phosphorylated IκB-α attenuates NF-κB p65 nuclear translocation, resulting in a decrease of p65 protein in the nucleus and an increase of p65 protein in the cytoplasm. These results indicated that shikonin inhibited TNF-α-induced NF-κB activation.
Metabolic inflammation (sepsis model): Shikonin, as a potential PKM2 inhibitor, reduces serum lactate and HMGB1 levels, and protects mice from lethal endotoxemia and sepsis.
Recent studies show that shikonin suppresses tumour growth in lung, ovarian, and other cancers through diverse mechanisms, including apoptosis induction, cell cycle arrest, inhibition of metastasis, necroptosis, and disruption of tumour metabolism. Its multi-targeted activity and relatively low systemic toxicity highlight shikonin as a compelling candidate for development as both a preventive agent and an adjunct to conventional cancer therapies.
The vast majority of oncology evidence for shikonin is preclinical — derived from in vitro (cell culture) and in vivo (animal) studies. The following is a representative sample of the cancer types studied:
Evidence further indicates that shikonin can enhance the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, thereby contributing to the reversal of therapeutic resistance.
Evidence strength (oncology): While numerous research investigations have been reported on the anticancer potential of shikonin, more research is needed to investigate its synergistic effects with conventional cancer therapies and to assess its clinical efficacy in robust trials. Due to a lack of clinical data, more clinical trials are vital to establish efficacy and safety in human patients. The current literature identifies shikonin as a promising dietary phytochemical with diverse anticancer activities, therapeutic synergy, and formulation advances, while highlighting the need for clinical studies to establish its translational potential. In summary, anticancer evidence is extensive but remains predominantly preclinical (in vitro and animal models); robust human clinical trial evidence is currently lacking.
Studies carried out over the past 30 years have provided a scientific basis for the use of Zicao which has been long employed in folk medicine to treat a variety of inflammatory and infectious diseases. In particular, shikonin has been shown to possess many diverse properties, including antioxidant, anti-inflammatory, antithrombotic, antimicrobial, and wound healing effects.
Intragastric administration of shikonin suppressed the swelling rate of ears in a mouse model of acute inflammation in a dose-dependent manner; the 20 mg/kg shikonin treatment exhibited the highest inhibitory effect. The inhibitory effect of shikonin at 20 mg/kg on inflammation was closely linked to the intestinal flora, whereby the microbiota phylum was altered in feces through 16S rDNA sequencing analysis, implying that shikonin improves gut microbiota structures and compositions to counteract inflammation.
Regarding atopic dermatitis, a human ex vivo study (not a clinical trial) provides partial human-derived data: The objective of a published study was to investigate the effect of shikonin on proinflammatory cytokines and chemokines in patients with atopic dermatitis. Ten patients with atopic dermatitis who were allergic to house dust mite (HDM) and seven healthy controls were recruited. Peripheral blood mononuclear cells were isolated, and CD14+ cells were further selected and differentiated to dendritic cells. Dendritic cells stimulated using Der p 2, the major HDM allergen, were co-treated with shikonin for 24 hours, and dexamethasone was used as a control. Culture supernatants were collected, and proinflammatory cytokine and chemokine concentrations were analyzed. Shikonin inhibited the expression of Der p 2-induced cytokines (IL-6, IL-9, and IL-17A) and chemokines in the dendritic cells of patients with atopic dermatitis, and its inhibitory effect on the expression of IL-9, MIP-1β, and CCL5 was stronger than that of dexamethasone.
Evidence strength (anti-inflammatory): Evidence is largely from animal models and in vitro studies. The atopic dermatitis study used human-derived cells in culture, not a randomized controlled trial. Overall, anti-inflammatory evidence is preliminary-to-moderate and mechanistically supported, but clinical trial data in humans are sparse.
Over the last four decades, shikonin and its derivatives have demonstrated antimicrobial, antioxidant, anti-inflammatory, wound healing, anticancer, antiulcer, anti-angiogenic, and granulated tissue-forming activity.
Shikonin exhibits potent antimicrobial activity, inhibiting the growth of pathogenic microorganisms such as Staphylococcus aureus, thereby reducing the risk of infection at the wound site and creating a favorable environment for healing. Shikonin also plays a critical role in accelerating wound healing by promoting the migration and proliferation of skin cells through the induction of epithelial–mesenchymal transition (EMT).
Shikonin is a major active chemical component extracted from Lithospermi Radix, an effective traditional herb in various types of wound healing. Shikonin can accelerate granulomatous tissue formation by the rat cotton pellet method and induce neovascularization in granulomatous tissue.
Shikonin can promote the formation of granulomatous tissue and induce the neovascularization of granulomatous tissue in the skin tissue of rats. Research suggests that L. erythrorhizon extract, in which derivatives of shikonin were identified, has the ability to protect skin from aging caused by oxidative stress.
Evidence strength (wound healing): Pre-clinical (rodent model) evidence is consistent and well replicated. There is a long tradition of topical use in TCM. Mechanistic in vitro data are robust. High-quality randomized controlled trial data in humans are not yet established for isolated shikonin preparations, though topical formulations have been used clinically in East Asian countries.
Shikonin has better antibacterial activity against S. aureus, and this could be linked to its chemical structure (i.e., naphthoquinone compound) since quinone has potent antibacterial activity. Shikonin and its naphthoquinone derivatives have been proved to be the active components that possess a wide spectrum of wound-healing, antitumor, antifungal, anti-HIV, antioxidant, and contraceptive activities.
Evidence strength (antimicrobial): Primarily in vitro. Animal and human clinical data specifically for antimicrobial endpoints are limited.
High anti-tyrosinase activity and antioxidant activity of shikonin were confirmed by molecular docking results and, among others, ABTS, hydroxyl, superoxide, and DPPH free radical scavenging activity. Research showed that alkannin, shikonin, and their derivatives when applied to oils can improve their antioxidant properties.
Evidence strength (antioxidant): In vitro evidence is consistent. In vivo and human clinical data remain limited.
Shikonin exerts therapeutic efficacies including cardiovascular protection and anti-obesity effects, mainly by regulating the NF-κB, PI3K/Akt/MAPKs, Akt/mTOR, TGF-β, GSK3β, and TLR4/Akt signaling pathways, NLRP3 inflammasome, reactive oxygen stress, and Bax/Bcl-2. Shikonin is also known for antithrombotic, neuroprotective, and antidiabetic pharmacological potential.
Evidence strength (cardiovascular/metabolic): Mechanistic and animal model data are available. Human evidence is currently absent.
The inhibitory effect of shikonin on inflammation was closely linked to the intestinal flora, whereby the microbiota phylum was altered in feces through a 16S rDNA sequencing analysis, implying that shikonin improves gut microbiota structures and compositions to counteract inflammation.
Evidence strength (gut microbiota): Animal model only. This is a nascent area of research with no clinical evidence to date.
In terms of pharmacokinetics, shikonin has an unfavorable oral bioavailability, 64.6% binding rate of plasma protein, and enhances some metabolic enzymes, particularly including cytochrome P450.
Although shikonin can be metabolized in the body when administered via any route, when given by the oral route, first-pass metabolism occurs along with a lower absorption rate at the intestine, which is not observed in other routes. This results in the decreased bioavailability of shikonin, and hence toxicity by the oral route is more minor compared to other modes of administration.
The primary metabolic pathway of shikonin involves hydroxylation of the naphthoquinone nucleus, followed by the formation of glucuronide conjugates that are excreted in bile and urine. Furthermore, in the human intestine, Bacteroides fragilis subsp. thetaotus can extensively metabolize shikonin into ten metabolites.
Dosages in the published literature vary widely by administration route, model system, and research objective. The following are doses as reported in the specific sources identified:
No standardized human dosing has been established in the peer-reviewed literature for oral or systemic shikonin preparations.
In regard to the toxicological effects, shikonin may potentially cause nephrotoxicity and skin allergy. Shikonin, as a glycolysis inhibitor, induces weight loss in animals and causes skin sensitization at low concentrations. It also promotes Ca2+ entry and induces eryptosis in humans.
Studies on the toxicity of this molecule in different species and with different administration routes are still missing and should be carried out.
Shikonin potently inhibited six CYP isoenzymes in both human and rat liver microsomes. Shikonin exhibited no time-dependent inhibition of CYP activities. Shikonin displayed different inhibition types on CYP isoenzymes. Shikonin displays strong inhibition against various CYP450 isoforms including CYP2C9, CYP2D6, and CYP3A4. From this study, it can be deduced that shikonin showed an inhibitory effect on tramadol metabolism via CYP2D6 and CYP3A4.
Shikonin may lead to toxicity in drug-drug interactions due to its atypical inhibitory effect on CYP. Considerable attention should be given to the issues related to the safety of shikonin in combination with other drugs via associated metabolic enzymes in vivo.
The heat and light stability of shikonin derivatives was studied, and it was found that the more photodegraded or thermally degraded a compound is, the more unstable it becomes. Based on the half-life, the compounds deoxyshikonin and isobutyrylshikonin were the most thermally unstable compared to other derivatives.
The pharmacodynamics and pharmacokinetics of shikonin have been validated by only a few clinical trials. The overall human safety profile for systemic or oral shikonin administration remains incompletely characterized, and peer-reviewed human clinical safety data are sparse. Topical use has a long traditional record in TCM, and lower doses of shikonin have been observed to be safe and well-tolerated. Topical formulations of shikonin have been applied in human studies without significant adverse effects.
Health conditions that Shikonin may help support.
Body systems that Shikonin may help support.
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