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| Mechanisms of Shikonin's Antimicrobial Action and Its Applications in Animal Production |
| WANG Yi-Ping1,2, ZHOU Xiao-Jie1, LIU Jing-Ya1, HUANG Xin-Li1, LAN Ying1, LIU Ben1,2,*, ZHENG Wen-Ya1,2 |
1 School of Life Sciences and Environmental Resources, Yichun University, Yichun 336000, China;
2 Research Center for Traditional Chinese Veterinary Medicine and Animal Embryo Engineering Technology, Yichun University, Yichun 336000, China |
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Abstract Shikonin, a highly liposoluble naphthoquinone compound isolated from the dried roots of Lithospermum erythrorhizon, has been demonstrated to possess multiple biological functions, including antimicrobial, anti-inflammatory, anti-heat stress, and wound-healing promoting activities. Given its unique bioactive properties, this compound exhibits significant application potential in green antibiotic-free fields such as alleviating transport stress in livestock and poultry, promoting animal wound repair, developing feed additives, advancing the development of antibiotic-free feed, and food preservation. Therefore, this article comprehensively reviewed the mechanisms of action of shikonin against pathogenic microorganisms and summarized its potential applications and research findings in livestock production, including its role in alleviating transport stress, promoting wound repair, and serving as a feed additive. The review provides a reference for the development and utilization of shikonin in animal production.
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Received: 05 June 2025
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Corresponding Authors:
*liubenres@163.com
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[1] 陈召阳, 陈瑞丰, 单毅, 等. 2025. 犬猫致伤伤口感染预防及治疗研究进展[J]. 中华预防医学杂志, 59(1):110-115.
(Chen Z Y, Chen R F, Shan Y.2025. Research progress on prevention and treatment of wound infections caused by dog and cat bites[J]. Chinese Journal of Preventive Medicine, 59(1):110-115.)
[2] 储蓄, 张军霞, 王晶. 2022. 4种中药单体与丁酸钠诱导猪宿主防御肽表达的协同效果研究[J]. 中国畜牧兽医, 49(10):4063-4074.
(Chu X, Zhang J X, Wang J.2022. Synergistic effect of four chinese herbal monomers and sodium butyrate on the expression of porcine host defense peptide[J]. China Animal Husbandry & Veterinary Medicine, 49(10):4063-4074.)
[3] 沈晓静, 袁文娟, 刘佳瑶, 等. 2023. 紫草化学成分及生物活性研究进展[J]. 中华中医药学刊, 41(11):102-110.
(Shen X J, Yuan W J, Liu J Y, et al.2023. Research progress on chemical components and biological activities of zicao (Arnebiae radix)[J]. Chinese Archives of Traditional Chinese Medicine, 41(11):102-110.)
[4] 杨燕琴. 2023. 雷公藤、紫草对茶花鸡2号公鸡肌肉品质及血清激素的影响[D]; 硕士学位论文, 云南农业大学, 导师:陶琳丽, pp. 37-48.
(Yang Y Q.2023. Effects of tripterygium wilfordii and radix angebiae on meat quality and serum hormones of chahua No. 2 rooster[D]. Thesis for M.S., Yunnan Agricultural University, Supervisor:Tao L L, pp. 37-48.)
[5] 章亮, 罗琼, 何欢欢, 等. 2020. 基于网络药理学的软紫草“凉血”在热射病防护上的药效学研究[J]. 中国药学杂志, 55(17):1425-1432.
(Zhang L, Luo Q, He H H, et al.2020. Network pharmacology study of Arnebia euchroma in the protective effect of heat stroke[J]. Chinese Pharmaceutical Journal, 55(17):1425-1432.)
[6] Abo Ghanima M M, Aljahdali N, Abuljadayel D A, et al.2023. Effects of dietary supplementation of amla, chicory and leek extracts on growth performance, immunity and blood biochemical parameters of broilers[J]. Italian Journal of Animal Science, 22(1):24-34.
[7] Ahmed K, Furusawa Y, Tabuchi Y, et al.2012. Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response[J]. International Journal of Hyperthermia, 28(1):1-8.
[8] Antimicrobial Resistance Collaborators.2022. Global burden of bacterial antimicrobial resistance in 2019:A systematic analysis[J]. Lancet, 399(10325):629-655.
[9] Arampatzis A S, Giannakoula K, Kontogiannopoulos K N, et al.2021a. Novel electrospun poly-hydroxybutyrate scaffolds as carriers for the wound healing agents alkannins and shikonins[J]. Regen Biomater, 8(3):rbab011.
[10] Arampatzis A S, Kontogiannopoulos K N, Theodoridis K, et al.2021b. Electrospun wound dressings containing bioactive natural products:Physico-chemical characterization and biological assessment[J]. Biomaterials Research, 25(1):23.
[11] Aziz U B A, Saoud A, Bermudez M, et al.2024. Targeted small molecule inhibitors blocking the cytolytic effects of pneumolysin and homologous toxins[J]. Nature Communications, 15(1):3537.
[12] Bohling M W, Henderson R A, Swaim S F, et al.2004. Cutaneous wound healing in the cat:A macroscopic description and comparison with cutaneous wound healing in the dog[J]. Veterinary Surgery, 33(6):579-587.
[13] Borde C, Escargueil A E, Marechal V.2023. Shikonin, an inhibitor of inflammasomes, inhibits Epstein-Barr virus reactivation[J]. Antiviral Research, 217:105699.
[14] Candelli M, Sacco Fernandez M, Triunfo C, et al.2025. Vibrio vulnificus-a review with a special focus on sepsis[J]. Microorganisms, 13(1):128.
[15] Connolly K R, Sweeney T, O'Doherty J V.2024. Sustainable nutritional strategies for gut health in weaned pigs:The role of reduced dietary crude protein, organic acids and butyrate production[J]. Animals (Basel), 15(1):66.
[16] Cui J, Xiang S, Zhang Q, et al.2025. Design, synthesis, and biological evaluation of 5,8-dimethyl shikonin oximes as SARS-CoV-2 M(pro) inhibitors[J]. Molecules, 30(6):1321.
[17] Fan C, Dong Y, Xie Y, et al.2015. Shikonin reduces TGF-beta1-induced collagen production and contraction in hypertrophic scar-derived human skin fibroblasts[J]. International Journal of Molecular Medicine, 36(4):985-991.
[18] Fan C, Zhang X, Upton Z.2018. Anti-inflammatory effects of shikonin in human periodontal ligament cells[J]. Pharmaceutical Biology, 56(1):415-421.
[19] Gao H, Liu L, Qu Z Y, et al.2011. Anti-adenovirus activities of shikonin, a component of Chinese herbal medicine in vitro[J]. Biological & Pharmaceutical Bulletin, 34(2):197-202.
[20] Gu C, Fan X, Yu W.2023. Functional diversity of mammalian small heat shock proteins:A review[J]. Cells, 12(15):1947.
[21] Gupta S, Singh A K, Kushwaha P P, et al.2021. Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies[J]. Journal of Biomolecular Structure and Dynamics, 39(12):4334-4345.
[22] Gurard-Levin Z A, Liu C, Jekle A, et al.2020. Evaluation of SARS-CoV-2 3C-like protease inhibitors using self-assembled monolayer desorption ionization mass spectrometry[J]. Antiviral Research, 182:104924.
[23] Han H, Sun W, Feng L, et al.2021. Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis[J]. PeerJ, 9:e10675.
[24] He Y, Luo K, Hu X, et al.2023. Antibacterial mechanism of shikonin against Vibrio vulnificus and its healing potential on infected mice with full-thickness excised skin[J]. Foodborne Pathog and Disease, 20(2):67-79.
[25] Huang H, Liao D, He B, et al.2023. Deoxyshikonin inhibited rotavirus replication by regulating autophagy and oxidative stress through SIRT1/FoxO1/Rab7 axis[J]. Microbial Pathogenesis, 178:106065.
[26] Huang L, Tang X, Yang F, et al.2021. Shikonin contributes to intestinal epithelial cell differentiation through PKM2/NRF2-mediated polyol pathway[J]. Pharmacological Research - Modern Chinese Medicine, 1:100004.
[27] Jiang Y, Yu B, Yang H, et al.2016. Shikonin inhibits intestinal calcium-activated chloride channels and prevents rotaviral diarrhea[J]. Frontiers in Pharmacology, 7:270.
[28] Jin Z, Du X, Xu Y, et al.2020. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors[J]. Nature, 582(7811):289-293.
[29] Karayannopoulou M, Loukopoulos P, Papazoglou L G, et al.2010. Naturally occurring isohexenylnaphthazarins and wound healing:Experimental study in dogs[J]. Journal of Cutaneous Medicine and Surgery, 14(2):62-70.
[30] Karayannopoulou M, Tsioli V, Loukopoulos P, et al.2011. Evaluation of the effectiveness of an ointment based on alkannins/shikonins on second intention wound healing in the dog[J]. Canadian Journal of Veterinary Research, 75(1):42-48.
[31] Katiyar R, Gonmei C, Deori S, et al.2025. Effect of heat stress on pig production and its mitigation strategies:A review[J]. Tropical Animal Health and Production, 57(3):139.
[32] Kim H, Shin H Y, Park M, et al.2024a. Exosome-like vesicles from lithospermum erythrorhizon callus enhanced wound healing by reducing LPS-Induced Inflammation[J]. Journal of Microbiology and Biotechnology, 35:e2410022.
[33] Kim Y G, Lee J H, Kim S H, et al.2024b. Inhibition of biofilm formation in Cutibacterium acnes, Staphylococcus aureus, and Candida albicans by the phytopigment shikonin[J]. International Journal of Molecular Sciences, 25(4):2426.
[34] Krasnikov N, Gulyukin A, Aliper T, et al.2024. Complete genome characterization by nanopore sequencing of rotaviruses A, B, and C circulating on large-scale pig farms in russia[J]. Virology Journal, 21(1):289.
[35] Lee Y S, Lee D Y, Kim Y B, et al.2015. The mechanism underlying the antibacterial activity of shikonin against methicillin-resistant Staphylococcus aureus[J]. Evidence-based Complementary and Alternative Medicine, 2015:520578.
[36] Li J, Li S, Li H, et al.2021a. Antibiofilm activity of shikonin against listeria monocytogenes and inhibition of key virulence factors[J]. Food Control, 120:107558.
[37] Li J, Zhou X, Zhang Y, et al.2021b. Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode[J]. Sci Bull (Beijing), 66(7):661-663.
[38] Li M Y, Xu Z T, Zhu C L, et al.2012. Effect of different derivatives of shikonin from lithospermum erythrorhizon against the pathogenic dental bacteria[J]. Current Pharmaceutical Analysis, 8(3):255-260.
[39] Li M-Y, Zhu L, Lai G-Y, et al.2014. The inhibition of acetylshikonin on bacteria and its trypsin-like protease and glycosidic enzyme may be essential to conquer periodontal ecological niche[J]. Letters in Drug Design & Discovery, 11(10):1162-1166.
[40] Li Q Q, Chae H S, Kang O H, et al.2022. Synergistic antibacterial activity with conventional antibiotics and mechanism of action of shikonin against methicillin-resistant Staphylococcus aureus[J]. International Journal Of Molecular Sciences, 23(14):7551.
[41] Liao Z, Yan Y, Dong H, et al.2016. Endogenous nitric oxide accumulation is involved in the antifungal activity of shikonin against Candida albicans[J]. Emerg Microbes Infect, 5(8):e88.
[42] Liao Z, Zhu Z, Li L, et al.2019. Metabonomics on candida albicans indicate the excessive H3K56ac is involved in the antifungal activity of shikonin[J]. Emerging Microbes & Infections, 8(1):1243-1253.
[43] Liu C, Zhang H, Cui X, et al.2023a. The effects of shikonin on the hypertrophic scar of rabbit ears via the TLR4/NF-kappaB signaling pathway[J]. Cellular and Molecular Biology, 69(9):161-166.
[44] Liu J X, Yang L, Wan Y, et al.2024. Small molecules accelerate skin wound healing:Shikonin efficacy and mechanism of action in mice[J]. International Journal of Morphology, 42(1):127-136.
[45] Liu Y, Wang Y, Kong J, et al.2023b. An effective antimicrobial strategy of colistin combined with the chinese herbal medicine shikonin against colistin-resistant Escherichia coli[J]. Microbiology Spectrum, 11(6):e0145923.
[46] Lu X, Tan K, Gong Q, et al.2024a. Positive effects of lithospermum erythrorhizon extract added to high soybean meal diet on growth, intestinal antioxidant capacity, intestinal microbiota, and metabolism of pearl gentian grouper[J]. Aquaculture Reports, 39:102500.
[47] Lu X, Wu Y, Peng Y, et al.2024b. Dietary lithospermum erythrorhizon ethanol extract alleviates soybean meal-induced enteritis by improving immune tolerance profile of pearl gentian grouper (Epinephelus fuscoguttatus female symbol x E. lanceolatus male symbol)[J]. Comparative Biochemistry and Physiology Part D Genomics Proteomics, 52:101335.
[48] Luo B, Ding X, Hu Y, et al.2025. Shikonin hastens diabetic wound healing by inhibiting M1 macrophage polarisation through the MAPK signaling pathway[J]. Molecular Immunology, 177:73-84.
[49] Luo Q, Ji X Y, Zhang L, et al.2023. Shikonin prevents mice from heat stroke-induced death via suppressing a trigger IL-17A on the inflammatory and oxidative pathways[J]. Biomed Pharmacother, 166:115346.
[50] Ma C, Hu Y, Townsend J A, et al.2020. Ebselen, disulfiram, carmofur, PX-12, tideglusib, and shikonin are nonspecific promiscuous SARS-CoV-2 main protease inhibitors[J]. ACS Pharmacology & Translational Science, 3(6):1265-1277.
[51] Machado N A F, Barbosa-Filho J A D, Martin J E, et al.2022. Effect of distance and daily periods on heat-stressed pigs and pre-slaughter losses in a semiarid region[J]. International Journal of Biometeorology, 66(9):1853-1864.
[52] Meifang L, Liming S, Wenxue Z, et al.2023. Study on antiviral mechanism of acetylshikonin against Herpes simplex virus type 2 in vitro[J]. Journal of Tropical Diseases and Parasitology, 21(4):204.
[53] Miao H, Zhao L, Li C, et al.2012. Inhibitory effect of shikonin on Candida albicans growth[J]. Biological & Pharmaceutical Bulletin, 35(11):1956-1963.
[54] Nomura R, Suehiro Y, Tojo F, et al.2024. Inhibitory effects of shikonin dispersion, an extract of lithospermum erythrorhizon encapsulated in beta-1,3-1,6 glucan, on Streptococcus mutans and non-mutans Streptococci[J]. International Journal of Molecular Sciences, 25(2):1075.
[55] Pang C, Chen J, Liu S, et al.2023a. In vitro antifungal activity of shikonin against candida albicans by inducing cellular apoptosis and necrosis[J]. Molecular Biology Reports, 50(2):1079-1087.
[56] Pang C, Chen J, Yang L, et al.2023b. Shikonin inhibits candida albicans biofilms via the ras1-cAMP-Efg1 signalling pathway[J]. International Journal of General Medicine, 16:2653-2662.
[57] Polonik S G, Krylova N V, Kompanets G G, et al.2019. Synthesis and screening of anti-HSV-1 activity of thioglucoside derivatives of natural polyhydroxy-1, 4-naphthoquinones[J]. Natural Product Communications, 14(6):1-7.
[58] Rodrigues T, Guardiola F A, Almeida D, et al.2025. Aquatic invertebrate antimicrobial peptides in the fight against aquaculture pathogens[J]. Microorganisms, 13(1):156.
[59] Shahrbabaki A S, Amini B, Ghorbani M, et al.2024. Dose-specific modulation of MAPK signaling by bioactive aromatic extract of onosma microcarpum during distinct phases of wound healing in a rat model[J]. Natural Product Communications, 20(8):1-13.
[60] Shilov S V, Ustenova G O, Kiyekbayeva L N, et al.2022. Component composition and biological activity of various extracts of Onosma gmelinii (boraginaceae)[J]. International Journal of Biomaterials, 2022:4427804.
[61] Shishodia S K, Shankar J.2020. Proteomic analysis revealed ROS-mediated growth inhibition of Aspergillus terreus by shikonin[J]. Journal of Proteomics, 224:103849.
[62] Song Y, Ding Q, Hao Y, et al.2023. Pharmacological effects of shikonin and its potential in skin repair:A review[J]. Molecules, 28(24):7950.
[63] Thakur R, Shishodia S K, Sharma A, et al.2024. Accelerating the understanding of Aspergillus terreus:Epidemiology, physiology, immunology and advances[J]. Current Research in Microbial Sciences, 6:100220.
[64] Tian M, Wu J, Du Q, et al.2025. Revealing the mechanisms of shikonin against diabetic wounds:A combined network pharmacology and in vitro investigation[J]. Journal of Diabetes Research, 2025(1):4656485.
[65] van Staaveren N, Pessoa J, Boyle L A, et al.2024. Description of patterns of ear and tail lesions during the grower-finisher period in a commercial pig farm[J]. Porcine Health Management?, 10(1):23.
[66] Vinaik R, Barayan D, Auger C, et al.2020. Regulation of glycolysis and the warburg effect in wound healing[J]. Journal of Clinical Investigation Insight, 5(17):e138949.
[67] Wan Y, Wang X, Zhang P, et al.2021. Control of foodborne Staphylococcus aureus by shikonin, a natural Extract[J]. Foods, 10(12):2954.
[68] Wang J, Chen M, Wang S, et al.2022. Identification of phytogenic compounds with antioxidant action that protect porcine intestinal epithelial cells from hydrogen peroxide induced oxidative damage[J]. Antioxidants (Basel), 11(11):2134.
[69] Wang J, Lyu W, Zhang W, et al.2021a. Discovery of natural products capable of inducing porcine host defense peptide gene expression using cell-based high throughput screening[J]. Journal of Animal Science and Biotechnology, 12(1):14.
[70] Wang J, Zhang W, Chu X, et al.2021b. Deoxyshikonin-Induced gene expression profile in porcine epithelial cells[J]. Frontiers in Veterinary Science, 8:711721.
[71] Watson M, Saitis T, Shareef R, et al.2023. Shikonin and alkannin inhibit ATP synthase and impede the cell growth in Escherichia coli[J]. International Journal of Biological Macromolecules, 253(Pt 4):127049.
[72] Woo J, Das R.2022. Binding mechanisms of shikonin derivatives targeting SARS-CoV-2 main protease[J]. The FASEB Journal, 36(S1):L7672.
[73] Wu T, Zhang Y M, Krishnan S, et al.2022. Bioactive small molecule enhances skin burn wound healing and hair follicle regeneration by activating PI3K/AKT signaling pathway:A preclinical evaluation in animal model[J]. Journal of Biomedical Nanotechnology, 18(2):463-473.
[74] Wu Z, Song J, Zhang Y, et al.2024. Inhibitory and preventive effects of Arnebia euchroma (royle) Johnst. root extract on Streptococcus mutans and dental caries in rats[J]. British Dental Journal Open, 10(1):15.
[75] Xue C, Dou J, Zhang S, et al.2024. Shikonin potentiates skin wound healing in sprague-dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis[J]. Journal of Gene Medicine, 26(1):e3633.
[76] Yan Y, Tan F, Miao H, et al.2019. Effect of shikonin against candida albicans biofilms[J]. Frontiers in Microbiology, 10:1085.
[77] Zagorodnyaya E B, Oskol'skii G I, Basharov A Y, et al.2013. Biopolymeric film containing bioactive naphthoquinone (shikonin) in combined therapy of inflammatory destructive lesions in the buccal mucosa[J]. Bulletin of Experimental Biology and Medicine, 156(2):232-235.
[78] Zhang Q, Wang M, Deng X, et al.2023. Shikonin promotes hypertrophic scar repair by autophagy of hypertrophic scar-derived fibroblasts[J]. Acta Cirurgica Brasileira, 38:e384623.
[79] Zhang R, Li G, Wu Y, et al.2024. Pathogenic mechanisms and potential applications of extracellular vesicles from periodontal pathogens in periodontitis[J]. Front Immunol, 15:1513983.
[80] Zhang Y, Gao H, Hu X, et al.2022. Structure-based discovery and structural basis of a novel broad-spectrum natural product against the main protease of Coronavirus[J]. Journal of Virology, 96(1):e0125321.
[81] Zhang Y, Han H, Qiu H, et al.2017. Antiviral activity of a synthesized shikonin ester against influenza A (H1N1) virus and insights into its mechanism[J]. Biomed Pharmacother, 93:636-645.
[82] Zhao X, Zhou Y, Wang L, et al.2017. Shikonin alleviates the biotoxicity produced by pneumococcal pneumolysin[J]. Life Sciences, 177:1-7. |
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