Targeting PIM1 by Bruceine D attenuates skin fibrosis via myofibroblast ferroptosis

Area of Science:

• Dermatology
• Molecular Biology
• Pharmacology

Background:

• Skin pan-fibrosis diseases like hypertrophic scar (HS), keloid scar (KS), and systemic sclerosis (SSc) significantly impact patient health and quality of life.
• Myofibroblasts are key effector cells in skin fibrosis pathogenesis.
• Elevated PIM1 expression is observed in fibrotic tissues and animal models.

Purpose of the Study:

• To investigate the role of serine/threonine kinase PIM1 in skin pan-fibrosis diseases.
• To identify potential therapeutic targets and agents for treating these conditions.
• To evaluate the efficacy of Bruceine D (BD) in mitigating skin fibrosis.

Main Methods:

• In vivo and in vitro experiments were conducted.
• PIM1 expression levels were analyzed in human fibrotic tissues and animal models.
• High-throughput screening identified Bruceine D (BD) as a PIM1 inhibitor.
• The effect of BD on the PIM1-KEAP1-NRF2 pathway and ferroptosis was assessed.
• Efficacy of BD was tested in multiple preclinical models of skin fibrosis.

Main Results:

• PIM1 was found to be upregulated in myofibroblasts of human HS, KS, and SSc tissues and in animal models.
• PIM1 overexpression enhanced profibrotic phenotypes in human hypertrophic scar fibroblasts (HSFs).
• Bruceine D (BD) directly binds to and inhibits PIM1, promoting HSF ferroptosis via the PIM1-KEAP1-NRF2 pathway.
• BD treatment effectively attenuated fibrotic phenotypes in mouse and rabbit ear models of hypertrophic scarring and bleomycin-induced skin fibrosis.

Conclusions:

• PIM1 is a common biomarker and therapeutic target for skin pan-fibrosis diseases.
• Bruceine D (BD) mitigates skin fibrosis by activating ferroptosis through PIM1 inhibition.
• BD demonstrates significant translational potential for clinical development in treating fibrotic conditions with elevated PIM1.