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
  • 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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