BET bromodomain inhibitors regulate keratinocyte plasticity

Area of Science:

• Dermatology
• Molecular Biology
• Drug Discovery

Background:

• Chronic skin ulcers are a significant unmet medical need due to impaired keratinocyte function.
• Keratinocyte plasticity is crucial for wound re-epithelialization but is lost in chronic wounds.
• Novel therapeutics are needed to restore keratinocyte function for effective wound healing.

Purpose of the Study:

• To identify small molecules that can restore keratinocyte plasticity and promote skin wound healing.
• To investigate the potential of bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi) as therapeutic agents for wound repair.

Main Methods:

• High-throughput phenotypic screening of primary keratinocytes to identify small-molecule regulators.
• In vitro assessment of keratinocyte activation and migration.
• Ex vivo analysis of human epidermis activation markers.
• In vivo evaluation of skin wound healing in animal models.

Main Results:

• BET protein family inhibitors (BETi) were identified as potent inducers of keratinocyte activation and migration in vitro.
• BETi treatment increased keratinocyte activation markers in human epidermis ex vivo.
• Transient low-dose BETi exposure significantly enhanced skin wound healing in vivo.
• The pro-healing effects of BETi were observed only after transient, low-dose administration.

Conclusions:

• BET inhibitors represent a novel class of compounds with the potential to treat non-healing skin ulcers.
• Targeting keratinocyte plasticity with BETi offers a promising therapeutic strategy for promoting skin wound re-epithelialization.
• The unique property of transient, low-dose exposure for BETi efficacy opens new avenues for their clinical application in wound care.