2. Academic Validation
  3. Isolinderalactone targets TNF-α/STAT3 inflammatory pathways to attenuate psoriasis-like dermatitis

Isolinderalactone targets TNF-α/STAT3 inflammatory pathways to attenuate psoriasis-like dermatitis

  • Eur J Pharmacol. 2026 Mar 28:1019:178733. doi: 10.1016/j.ejphar.2026.178733.
Shuya Sun 1,  Hao Shen 1,  Yihe Liu 2,  Weijian He 1,  Di Hua 1,  Zhongya Song 1,  Ran Mo 1,  Linghan Hu 1,  Zhiming Chen 1,  Yongcheng Zhu 1,  Yunlong Shan 3,  Yong Yang 4,  Ruiyu Xiang 5
Affiliations

Affiliations

  • 1 Genetic Skin Disease Center, Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 2 Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
  • 4 Genetic Skin Disease Center, Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. Electronic address: [email protected].
  • 5 Genetic Skin Disease Center, Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. Electronic address: [email protected].
PMID: 41795538 DOI: 10.1016/j.ejphar.2026.178733
Abstract

Background: Given the proinflammatory cascade elicited by tumor necrosis factor-α (TNF-α) in psoriasis, multiple TNF-α-targeted biologics have been developed for psoriasis treatment. Although systemic macromolecular biologics are widely used, a crucial therapeutic gap remains for mild-to-moderate psoriasis, underscoring an unmet need for more effective topical drugs suppressing TNF-induced inflammatory signaling.

Objective: To identify a novel potent natural small-molecule drug suppressing TNF-induced inflammatory signaling and elucidate its therapeutic mechanism in psoriasis.

Methods: First, candidate small-molecule drugs were screened out through a high-throughput screening platform. Next, the therapeutic effect of Isolinderalactone was evaluated through topical application in the imiquimod (IMQ)-induced psoriasis-like mouse model. Subsequently, RNA Sequencing (RNA-seq) analysis of TNF-α-stimulated HaCaT cells and epidermis of IMQ-treated mice identified key transcriptomic alterations induced by Isolinderalactone treatment. Finally, anti-psoriasis effects and underlying mechanisms of Isolinderalactone were verified in both in vivo and in vitro experiments.

Results: Isolinderalactone was identified as a potent drug suppressing TNF-related signaling with low cytotoxicity. Topical application of Isolinderalactone significantly alleviated IMQ-induced psoriasis-like dermatitis. Conjoint analysis of RNA-seq for TNF-α-stimulated HaCaT cells and epidermis from lesions of IMQ-treated mice revealed Isolinderalactone downregulated the expression of TNF-α, interleukin-17 (IL-17) and S100-related inflammatory factors in epidermal keratinocytes. Mechanistically, Isolinderalactone significantly inhibited the TNF-α/STAT3 inflammatory pathways in epidermal keratinocytes and exerted an anti-inflammatory effect.

Conclusion: Isolinderalactone exhibits anti-inflammatory activity through multiple mechanisms, highlighting the potential of topical Isolinderalactone therapy for mild-to-moderate psoriasis.

Keywords

Isolinderalactone; Psoriasis; STAT3; Small-molecule drugs; TNF-α.

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