Network pharmacology-guided discovery of avicularin from Euphorbia humifusa Willd. targeting IL-17 signaling in psoriasis

Abstract

Despite therapeutic advances, long-term psoriasis management remains challenged by cost, immunogenicity, and administration barriers. Although the anti-inflammatory properties of avicularin (AL) are recognized, its direct targeting of IL-17RA and its therapeutic efficacy in psoriasis remain unreported. Here, we established the efficacy of Euphorbia humifusa Willd. (EH) in a psoriasis mouse model, then used an integrated strategy combining network pharmacology, RNA-seq, and surface plasmon resonance-mass spectrometry (SPR-MS) to assess its pharmacodynamic material basis. This systematic approach identified the IL-17 pathway as the primary mechanism, and IL-6, CXCL10, and IL-17RA as key targets. On the basis of these key targets, SPR-MS screened seven candidate compounds from EH, among which AL was confirmed as a key IL-17RA-targeting bioactive compound. Subsequent validation demonstrated that AL dose-dependently ameliorated psoriatic lesions and downregulated key IL-17 pathway effectors, including IL-17RA, IL-6, and CXCL10 ( p < 0.05). Direct binding between AL and IL-17RA was subsequently confirmed through bio-layer interferometry, SPR-MS re-screening, and molecular docking. Our findings not only establish AL as a promising oral IL-17RA-targeted agent but also delineate a robust strategy that may aid in the systematic discovery of active natural compounds.

Keywords

Psoriasis / Euphorbia humifusa Willd. / Network pharmacology / RNA-seq / SPR-MS / Avicularin

References

[1] Gelfand JM: Psoriasis - More Progress but More Questions. New England Journal of Medicine 2024, 390: 561-562.

[2] Al-Horani R, Chui T, Hamad B: The Pipeline and Market for Psoriasis Drugs. Nature Reviews Drug Discovery 2024, 23: 492-493.

[3] Guo J, Zhang H, Lin W, Lu L, Su J, Chen X: Signaling Pathways and Targeted Therapies for Psoriasis. Signal Transduction and Targeted Therapy 2023, 8: 1-38.

[4] Sieminska I, Pieniawska M, Grzywa TM: The Immunology of Psoriasis-Current Concepts in Pathogenesis. Clinical Reviews in Allergy & Immunology 2024, 66: 164-191.

[5] Ferrara F, Verduci C, Laconi E, Mangione A, Dondi C, Del Vecchio M, et al.: Therapeutic Advances in Psoriasis: From Biologics to Emerging Oral Small Molecules. Antibodies 2024, 13: 76.

[6] Koycheva IK, Marchev AS, Stoykova ID, Georgiev MI: Natural Alternatives Targeting Psoriasis Pathology and Key Signaling Pathways: A Focus on Phytochemicals. Phytochemistry Reviews 2023, 24: 2147-2173.

[7] Balato A, Burlando M, Campanati A, Costanzo A, Chiricozzi A, Gisondi P, et al.: Strategies for Optimal Use of Biological Therapies in Managing Psoriasis: Focus on Secukinumab. Dermatology and Therapy 2025, 15: 3089-3108.

[8] Konakanchi VC, Kar BR, Sathishkumar D, Tahiliani S, Parthasarathi A, Neema S, et al.: Small Molecules in the Management of Psoriasis and Psoriatic Arthritis. Indian Journal of Dermatology 2024, 69: 249-255.

[9] Xue T, Gong S, Xie TH, Li WJ, Huang JP: Development Status and Trend of Traditional Chinese Medicine Database. TMR Modern Herbal Medicine 2022, 5: 19-26.

[10] Wu X, Ma GL, Chen HW, Zhao ZY, Zhu ZP, Xiong J, et al.: Antibacterial and Antibiofilm Efficacy of the Preferred Fractions and Compounds from Euphorbia Humifusa (Herba Euphorbiae Humifusae) against Staphylococcus Aureus . Journal of Ethnopharmacology 2023, 306: 116177.

[11] Alimujiang A, Wang H, Chen L, Kang Y, Zhao J, Wei W, et al.: Euphorbia Humifusa Willd. Extract Alleviates Imiquimod-Induced Psoriasis-like Skin Lesions in Mice by Modulating the IL-17 Signaling Pathway . Journal of Ethnopharmacology 2025, 350: 120030.

[12] Huang PZ, Yang HY, Zhang LJ, Sun Y, Li Y, Gao K: Anti-Inflammatory Activities of Triterpenoids from Euphorbia Humifusa Willd. Phytochemistry Letters 2023, 54: 129-132.

[13] Lee SG, Kang H: In Vitro Adipocyte Differentiation Inhibition and In Vivo Effects on Lipid Metabolism in High-Fat Diet-Induced Obesity of Euphorbia Humifusa . Journal of Microbiology and Biotechnology 2024, 34: 387-398.

[14] Yang Y, Sheng D, Shi J, Xiao L, Wang Z, Yin Z, et al.: Avicularin Alleviates Osteoporosis-Induced Implant Loosening by Attenuating Macrophage M1 Polarization via Its Inhibitory Effect on the Activation of NF-κB . Biomedicine & Pharmacotherapy 2023, 158: 114113.

[15] Qiu T, Shi JX, Cheng C, Jiang H, Ruan HN, Li J, et al.: Avicularin Attenuates Lead-Induced Impairment of Hepatic Glucose Metabolism by Inhibiting the ER Stress-Mediated Inflammatory Pathway. Nutrients 2022, 14: 4806.

[16] Qiu T, Shi JX, Cheng C, Jiang H, Ruan HN, Li J, et al.: Hepatoprotective Effect of Avicularin on Lead-Induced Steatosis, Oxidative Stress, and Inflammation in Mice Associated with the MAPK/HSP60/NLRP3 and SREBP1c Pathway. Toxicology Research 2023, 12: 417-424.

[17] Lee WY, Park KI, Bak SB, Lee S, Bae SJ, Kim MJ, et al.: Evaluating Current Status of Network Pharmacology for Herbal Medicine Focusing on Identifying Mechanisms and Therapeutic Effects. Journal of Advanced Research 2024, 76: 799-815.

[18] Li L, Yang L, Yang L, He C, He Y, Chen L, et al.: Network Pharmacology: A Bright Guiding Light on the Way to Explore the Personalized Precise Medication of Traditional Chinese Medicine. Chinese Medicine 2023, 18: 146.

[19] Li X, Liu Z, Liao J, Chen Q, Lu X, Fan X: Network Pharmacology Approaches for Research of Traditional Chinese Medicines. Chinese Journal of Natural Medicines 2023, 21: 323-332.

[20] Wang Y, Xu T, Chen X, Ye Y, Liu L, Wang Y, et al.: Network Pharmacology and Molecular Docking Approach to Investigate the Mechanism of a Chinese Herbal Formulation Yougui Pills against Steroid-Related Osteonecrosis of the Femoral Head. Arabian Journal of Chemistry 2024, 17: 105609.

[21] Zhai Y, Liu L, Zhang F, Chen X, Wang H, Zhou J, et al.: Network Pharmacology: A Crucial Approach in Traditional Chinese Medicine Research. Chinese Medicine 2025, 20: 8.

[22] Li Q, Xiang Y, Zhang Z, Qu X, Wu J, Fu J, et al.: An Integrated RNA-Seq and Network Pharmacology Approach for Exploring the Preventive Effect of Corydalis Bungeana Turcz. Extract and Acetylcorynoline on LPS-Induced Acute Lung Injury . Journal of Ethnopharmacology 2024, 318: 117048.

[23] Wang C, Lin J, Xie H, Chen L, Chen P, Wu L, et al.: Study on Analgesic Effect of Shentong Zhuyu Decoction in Neuropathic Pain Rats by Network Pharmacology and RNA-Seq. Journal of Ethnopharmacology 2024, 330: 118189.

[24] Zhang P, Zhang D, Zhou W, Wang L, Wang B, Zhang T, et al.: Network Pharmacology: Towards the Artificial Intelligence-Based Precision Traditional Chinese Medicine. Briefings in Bioinformatics 2024, 25: bbad518.

[25] Zhang Y, Wang D, Wang X, Ma H, Liu Y, Hong Z, et al.: A Dual-Target SPR Screening System for Simultaneous Ligand Discovery of SARS-CoV-2 Spike Protein and Its Receptor ACE2 from Chinese Herbs. Journal of Pharmaceutical and Biomedical Analysis 2024, 245: 116142.

[26] Xie J, Li XD, Li M, Zhu HY, Cao Y, Zhang J, et al.: Advances in Surface Plasmon Resonance for Analyzing Active Components in Traditional Chinese Medicine. Journal of Pharmaceutical Analysis 2024, 14: 100983.

[27] Deng R, Zong G, Wang X, Yue B, Cheng P, Tao R, et al.: Promises of Natural Products as Clinical Applications for Cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2025, 1880: 189241.

[28] Xun Y, Chen G, Tang G, Zhang C, Zhou S, Fong TL, et al.: Traditional Chinese Medicine and Natural Products in Management of Hepatocellular Carcinoma: Biological Mechanisms and Therapeutic Potential. Pharmacological Research 2025, 215: 107733.

[29] Zeng M, Feng A, Ren Y, Zhang Q, Wang R, Zhang B, et al.: Salvia Miltiorrhiza Bunge Extract and Przewalskin Ameliorate Bleomycin-Induced Pulmonary Fibrosis by Inhibition of Apoptosis, Oxidative Stress and Collagen Deposition via the TGF-β1 Pathway . Phytomedicine 2024, 125: 155339.

[30] Bharadwaj R, Lusi CF, Mashayekh S, Nagar A, Subbarao M, Kane GI, et al.: Methotrexate Suppresses Psoriatic Skin Inflammation by Inhibiting Muropeptide Transporter SLC46A2 Activity. Immunity 2023, 56: 998-1012.

[31] Tang D, Chen M, Huang X, Zhang G, Zeng L, Zhang G, et al.: SRplot: A Free Online Platform for Data Visualization and Graphing. PLoS One 2023, 18: e0294236.

[32] Mastorino L, Dapavo P, Burzi L, Rosset F, Giunipero di Corteranzo I, Leo F, et al.: Drug Survival, Effectiveness, and Safety of Brodalumab for Moderate-to-Severe Psoriasis up to 3 Years. Journal of the American Academy of Dermatology 2024, 63: 922-928.

[33] Qiu YY, Zhang J, Zeng FY, Zhu YZ: Roles of the Peroxisome Proliferator-Activated Receptors (PPARs) in the Pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD). Pharmacological Research 2023, 192: 106786.

[34] Merrheim J, Villegas J, Van Wassenhove J, Khansa R, Berrih-Aknin S, le Panse R, et al.: Estrogen, Estrogen-like Molecules and Autoimmune Diseases. Autoimmunity Reviews 2020, 19: 102468.

[35] Li Y, Guo N, Zhao Y, Chen J, Zhao J, Bian J, et al.: IL-17A Activates JAK/STAT Signaling to Affect Drug Metabolizing Enzymes and Transporters in HepaRG Cells. Molecular Immunology 2024, 175: 55-62.

[36] Subudhi I, Konieczny P, Prystupa A, Castillo RL, Sze-Tu E, Xing Y, et al.: Metabolic Coordination between Skin Epithelium and Type 17 Immunity Sustains Chronic Skin Inflammation. Immunity 2024, 57: 1665-1680.e7.

[37] Chan TC, Lee MS, Huang WC, Chang WY, Krueger JG, Tsai TF: Capsaicin Attenuates Imiquimod-Induced Epidermal Hyperplasia and Cutaneous Inflammation in a Murine Model of Psoriasis. Biomedicine & Pharmacotherapy 2021, 141: 111950.

[38] Han YJ, Chung HS, Hwang HS: Ellagic Acid Suppresses β-Defensin2 Antimicrobial Peptide and CCL20 Chemokine in Psoriasis-like HaCaT Human Keratinocyte. Advances in Traditional Medicine 2025, 25: 723-733.

[39] Wang M, Ma X, Gao C, Luo Y, Fei X, Zheng Q, et al.: Rutin Attenuates Inflammation by Downregulating AGE-RAGE Signaling Pathway in Psoriasis: Network Pharmacology Analysis and Experimental Evidence. International Immunopharmacology 2023, 125: 111033.

[40] Wu P, Liu Y, Zhai H, Wu X, Liu A: Rutin Alleviates Psoriasis-Related Inflammation in Keratinocytes by Regulating the JAK2/STAT3 Signaling. Skin Research and Technology 2024, 30: e70011.

[41] Meng X, Zheng S, Yin Z, Wang X, Yang D, Zou T, et al.: Apigenin Ameliorates Imiquimod-Induced Psoriasis in C57BL/6J Mice by Inactivating STAT3 and NF-κB. Food Science and Human Wellness 2024, 13: 211-224.

[42] Singh VK, Sahoo D, Agrahari K, Khan A, Mukhopadhyay P, Chanda D, et al.: Anti-Inflammatory, Anti-Proliferative and Anti-Psoriatic Potential of Apigenin in RAW 264.7 Cells, HaCaT Cells and Psoriasis like Dermatitis in BALB/c Mice. Life Sciences 2023, 328: 121909.

[43] Zawawi NA, Ahmad H, Madatheri R, Fadilah NIM, Maarof M, Fauzi MB: Flavonoids as Natural Anti-Inflammatory Agents in the Atopic Dermatitis Treatment. Pharmaceutics 2025, 17: 261.

[44] Jug A, Bratkovi T, Ilaš J: Biolayer Interferometry and Its Applications in Drug Discovery and Development. TrAC Trends in Analytical Chemistry 2024, 176: 117741.

[45] Guo M, Zhu F, Qiu W, Qiao G, Law BYK, Yu L, et al.: High-Throughput Screening for Amyloid-β Binding Natural Small-Molecules Based on the Combinational Use of Biolayer Interferometry and UHPLC-DAD-Q/TOF-MS/MS. Acta Pharmaceutica Sinica B 2022, 12: 1723-1739.

[46] Babaei N, Gill M, Cervantes M, Kim D, Yang S, Wu JJ: Brodalumab for Moderate-to-Severe Psoriasis: A Comprehensive Review of Efficacy, Safety, and Clinical Positioning. Biologics: Targets and Therapy 2025, 19: 415-422.

[47] Gosia M, Doshi G, Bagwe Parab S, Godad A: Innovative Approaches to Psoriasis: Small Molecules Targeting Key Signaling Pathways. Immunological Investigations 2025, 54: 457-493.

[48] Azimi SI, Jafarzadeh A, Goodarzi A: Systematic Review of Comparative Studies on Emerging Psoriasis Treatments: Comparing Biologics with Biologics, Small Molecule Inhibitors with Small Molecule Inhibitors, and Biologics with Small Molecule Inhibitors. Inflammopharmacology 2025, 33: 2377-2407.

[49] Wang Y, Liu M, Chen S, Wu Q: Avicularin Inhibits Cell Proliferation and Induces Cell Apoptosis in Cutaneous Squamous Cell Carcinoma. Experimental and Therapeutic Medicine 2020, 19: 1065-1071.

[50] Tu Z, Wei W, Zeng F, Wang W, Zhang Y, Zhang Y, et al.: IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway. The American Journal of Pathology 2024, 194: 708-720.

[51] Zou ZL, Sun MH, Yin WF, Yang L, Kong LY: Avicularin Suppresses Cartilage Extracellular Matrix Degradation and Inflammation via TRAF6/MAPK Activation. Phytomedicine 2021, 91: 153657.

[52] Zhou X, Xie J, Yu S, Li S, Chi C: Molecular and Functional Characterization of IL-17R Signaling Pathway-Related Genes in Cuttlefish Sepiella Japonica: Identification, Expression Pattern and Protein Interaction . Aquaculture 2026, 612: 743295.

[53] Kotik M, Kulik N, Valentová K: Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed Reactions: Prospects for Green Chemistry. Journal of Agricultural and Food Chemistry 2023, 71: 14890-14910.

[54] Xie L, Deng Z, Zhang J, Dong H, Wang W, Xing B, et al.: Comparison of Flavonoid O-Glycoside, C-Glycoside and Their Aglycones on Antioxidant Capacity and Metabolism during In Vitro Digestion and In Vivo. Foods 2022, 11: 882.

[55] Ali AU, Khallaf ISA, Kamel AA, Badran AY, Gomaa AS, El faham TH, et al.: Impact of Quercetin Spanlastics on Livin and Caspase-9 Expression in the Treatment of Psoriasis Vulgaris. Journal of Drug Delivery Science and Technology 2022, 76: 103809.

[56] Zhang Y, Gong S, Liu L, Shen H, Liu E, Pan L, et al.: Cyclodextrin-Coordinated Liposome-in-Gel for Transcutaneous Quercetin Delivery for Psoriasis Treatment. ACS Applied Materials & Interfaces 2023, 15: 40228-40240.

[57] Liu Q, Liu J, Zheng Y, Lei J, Huang J, Liu S, et al.: Quercetin Mediates the Therapeutic Effect of Centella Asiatica on Psoriasis by Regulating STAT3 Phosphorylation to Inhibit the IL-23/IL-17A Axis. Nan Fang Yi Ke Da Xue Xue Bao 2025, 45: 90-99.

[58] Ma J, Wang F, Wang L, Wang Y, Wu D, Jiang W, et al.: Inhibition of PI3K/AKT/GLUT1 Signaling Pathway by Quercetin in the Treatment of Psoriasis. Frontiers in Bioscience-Landmark 2025, 30: 26884.

[59] Sabbadin C, Graziani A, Bavaresco A, Mazzeo P, Tizianel I, Ceccato F, et al.: Pseudohyperaldosteronism Due to Licorice: A Practice-Based Learning from a Case Series. International Journal of Molecular Sciences 2024, 25: 7454.

[60] Li WX, Lu YF, Wang F, Ai B, Jin SB, Li S, et al.: Application of 18β-Glycyrrhetinic Acid in the Structural Modification of Natural Products: A Review. Molecular Diversity 2025, 29: 739-781.

[61] Wei J, Zhang J, Hu F, Zhang W, Wu Y, Liu B, et al.: Anti-Psoriasis Effect of 18β-Glycyrrhetinic Acid by Breaking CCL20/CCR6 Axis through Its Vital Active Group Targeting GUSB/ATF2 Signaling. Phytomedicine 2024, 128: 155524.

[62] Kadagothy H, Nene S, Amulya E, Vambhurkar G, Rajalakshmi AN, Khatri DK, et al.: Perspective Insights of Small Molecules, Phytoconstituents and Biologics in the Management of Psoriasis: A Focus on Targeting Major Inflammatory Cytokine Pathways. European Journal of Pharmacology 2023, 947: 175668.

[63] Figueira O, Pereira V, Castilho PC: A Two-Step Approach to Orange Peel Waste Valorization: Consecutive Extraction of Pectin and Hesperidin. Foods 2023, 12: 3834.

[64] Ji Z, Deng W, Chen D, Liu Z, Shen Y, Dai J, et al.: Recent Understanding of the Mechanisms of the Biological Activities of Hesperidin and Hesperetin and Their Therapeutic Effects on Diseases. Heliyon 2024, 10: e26862.

[65] Kumar RM, Kumar H, Bhatt T, Jain R, Panchal K, Chaurasiya A, et al.: Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics. Pharmaceuticals 2023, 16: 196.

[66] Pérez-Valero Á, Magadán-Corpas P, Ye S, Serna-Diestro J, Sordon S, Hus E, et al.: Antitumor Effect and Gut Microbiota Modulation by Quercetin, Luteolin, and Xanthohumol in a Rat Model for Colorectal Cancer Prevention. Nutrients 2024, 16: 1161.

[67] Sajid M, Channakesavula CN, Stone SR, Kaur P: Synthetic Biology towards Improved Flavonoid Pharmacokinetics. Biomolecules 2021, 11: 754.

[68] Hu L, Luo Y, Yang J, Cheng C: Botanical Flavonoids: Efficacy, Absorption, Metabolism and Advanced Pharmaceutical Technology for Improving Bioavailability. Molecules 2025, 30: 1184.

[69] Li Y, Cheng Y, Cai Y, Duan Z, Xu H, Huang Y, et al.: Novel Small-Molecule Treatment and Emerging Biological Therapy for Psoriasis. Biomedicines 2025, 13: 781.

[70] Shen T, Wang X, Zhang X, Pei J, Wang Z, Li Q, et al.: Engineering of Flavonoid 3′-O-Methyltransferase for Improved Biomodification of Fisetin in Escherichia Coli . Journal of Agricultural and Food Chemistry 2025, 73: 11132-11145.

[71] Wang J, Chen C, Guo Q, Gu Y, Shi TQ: Advances in Flavonoid and Derivative Biosynthesis: Systematic Strategies for the Construction of Yeast Cell Factories. ACS Synthetic Biology 2024, 13: 2667-2683.

[72] Cai J, Chen C, Wang J, Zhang X, Cui Y, Zhu Q, et al.: PROTAC: A Revolutionary Technology Propelling Small Molecule Drugs into the next Golden Age. Frontiers in Oncology 2025, 15: 1676414.