Targeting TGF-β1/miR-21 Pathway in Keratinocytes Reveals Protective Effects of Silymarin on Imiquimod-Induced...

Area of Science:

• Dermatology and Molecular Biology
• Investigating molecular mechanisms of skin homeostasis and disease pathology.

Background:

• Epidermal cells rely on integrated signals for skin homeostasis, with the TGF-β1/miR-21-5p pathway being crucial and often dysregulated in skin conditions.
• Identifying therapeutic compounds that can modulate this pathway is essential for developing treatments for skin diseases.

Purpose of the Study:

• To screen medicinal plant extracts for compounds that modulate the TGF-β1/miR-21-5p signaling pathway in keratinocytes.
• To elucidate the molecular mechanisms by which silymarin impacts keratinocyte function and inflammatory responses.

Main Methods:

• Screening of plant extracts using a miR-ON RILES luciferase reporter system in TGF-β1-treated keratinocytes.
• Utilizing Argonaute 2 immunoprecipitation, RT-qPCR, and RNA-sequencing to analyze silymarin's effects on miR-21-5p expression and transcriptomic profiles.
• In vivo studies involving topical application of silymarin in a mouse model of psoriasiform lesions.

Main Results:

• Silymarin was identified as a potent regulator of miR-21-5p expression via a noncanonical TGF-β1 pathway.
• Silymarin influenced keratinocyte differentiation, cell cycle progression, and lipid metabolism, impacting Notch3, PPARγ, and NF-κB signaling.
• Topical silymarin application reduced imiquimod-induced psoriasiform lesions in mice, normalizing markers of inflammation, proliferation, differentiation, and lipid metabolism.

Conclusions:

• Silymarin demonstrates significant potential as a therapeutic agent for skin diseases characterized by miR-21-5p dysregulation.
• The multifaceted effects of silymarin on keratinocyte biology offer a novel approach to managing inflammatory skin conditions like psoriasis.