Cellular Senescence in Skin Wound Repair: Dual Roles and Senotherapeutic Interventions

Skin wound repair is a complex process involving numerous signalling pathways in various cell types. Cellular senescence (CS), described as a proliferative limit, has dual implications in this process. In acute wounds, transient cellular senescence acts as a beneficial mechanism that facilitates tissue repair through the controlled secretion of the senescence-associated secretory phenotype (SASP), promoting immune cell recruitment, myofibroblast differentiation and angiogenesis. In contrast, chronic wound settings, which are frequently associated with pathological conditions including type 2 diabetes, persistent hypoxia and advanced age, promote the buildup of senescent cells and impair their immune-mediated elimination. This generates a cycle of chronic inflammation through sustained SASP secretion, resulting in altered keratinocyte migration, dysfunctional fibroblast activity, abnormal extracellular matrix remodelling and healing failure. The therapeutic landscape targeting CS is rapidly evolving: senolytic approaches demonstrate efficacy in eliminating senescent cells, while senomorphic strategies effectively modulate the SASP without eliminating senescent cells. This review summarises the multifaceted involvement of CS in the healing cascade, focusing on molecular mechanisms and current senotherapeutic evidence. This analysis is crucial for developing targeted therapies that preserve the beneficial functions of CS while counteracting its pathological effects in chronic wounds and age-related tissue dysfunction.