An innovative targeted therapy for fluoroscopy-induced chronic radiation dermatitis

Area of Science:

• Dermatology
• Molecular Biology
• Oncology

Background:

• Fluoroscopy-induced chronic radiation dermatitis (FICRD) presents a significant clinical challenge due to its delayed onset and progressive nature.
• Current treatment strategies for FICRD are limited, necessitating research into underlying mechanisms for effective therapeutic development.

Purpose of the Study:

• To investigate the molecular mechanisms of FICRD using RNA-seq analysis.
• To identify potential therapeutic targets for FICRD based on identified molecular pathways.

Main Methods:

• RNA-sequencing analysis of mild damaged skin specimens from FICRD patients.
• Investigated the role of the Hippo pathway and its effector YAP1 in keratinocyte protection.
• Examined the mechanism of exosome-mediated intercellular communication involving YAP1.
• Assessed the therapeutic potential of targeting YAP1 downstream gene NR3C1 (glucocorticoid receptor) in vitro and in vivo.

Main Results:

• The Hippo pathway, particularly YAP1, was identified as dysregulated in FICRD.
• Radiation-induced YAP1 in keratinocytes promotes DNA repair and inhibits fibrosis through exosomal transfer.
• YAP1 positively regulates NR3C1, encoding the glucocorticoid receptor.
• Targeting NR3C1 with prednisolone demonstrated therapeutic potential in preclinical models and FICRD patients.

Conclusions:

• The study highlights the critical role of YAP1 in FICRD pathogenesis and its protective functions.
• Targeting the YAP1-NR3C1 axis, specifically the glucocorticoid receptor, offers a promising therapeutic strategy for FICRD.