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

Area of Science:

• Dermatology and immunology
• Pharmacology and drug discovery
• Molecular biology

Background:

• Psoriasis involves a pro-inflammatory cascade driven by tumor necrosis factor-alpha (TNF-α).
• Existing TNF-α-targeted biologics are systemic and leave a therapeutic gap for mild-to-moderate psoriasis.
• There is a need for effective topical treatments that suppress TNF-induced inflammatory signaling.

Purpose of the Study:

• Identify a novel, potent natural small-molecule drug for psoriasis treatment.
• Elucidate the therapeutic mechanisms of the identified drug in suppressing TNF-induced inflammatory signaling.

Main Methods:

• High-throughput screening identified candidate small molecules.
• Isolinderalactone's efficacy was assessed via topical application in an imiquimod (IMQ)-induced psoriasis-like mouse model.
• RNA sequencing (RNA-seq) analyzed transcriptomic changes in TNF-α-stimulated cells and mouse epidermis to determine mechanisms.

Main Results:

• Isolinderalactone demonstrated potent TNF-related signaling suppression with low cytotoxicity.
• Topical Isolinderalactone significantly alleviated IMQ-induced psoriasis-like dermatitis.
• Isolinderalactone downregulated key inflammatory factors (TNF-α, IL-17, S100) and inhibited the TNF-α/STAT3 pathway in epidermal keratinocytes.

Conclusions:

• Isolinderalactone exhibits significant anti-inflammatory activity via multiple mechanisms.
• Topical Isolinderalactone shows potential as a novel therapy for mild-to-moderate psoriasis.
• The study highlights a promising natural compound for targeted topical psoriasis treatment.