Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.

尽管大多数急性皮肤伤口愈合迅速，但无法愈合的皮肤溃疡代表着日益增长且大量未满足的医疗需求，迫切需要有效的治疗方法。角质形成细胞通过转变为激活的迁移状态使伤口重现以重建表皮屏障，但这种能力在功能失调的慢性伤口中丧失。角质形成细胞可塑性的小分子调节剂具有原位逆转角质形成细胞功能障碍的潜力，可以为皮肤伤口愈合提供一种新的治疗方法。利用原代角质形成细胞的高通量表型筛选，我们鉴定了此类小分子，包括溴结构域和额外末端结构域 (BET) 蛋白家族抑制剂 (BETi)。BETi 在体外诱导角质形成细胞持续激活、迁移状态，增加离体人表皮中的活化标记物并增强体内皮肤伤口愈合。我们的研究结果表明 BETi 在促进皮肤伤口的角质形成细胞再上皮化方面具有潜在的临床用途。重要的是，BETi 的这种新特性仅在短暂的低剂量暴露后观察到，揭示了此类化合物的新潜力。