Deciphering keloid formation and treatment: insights from mechanobiology.

Abstract

Keloids are benign fibroproliferative disorders characterized by raised dermal lesions that extend beyond original wound margins, often causing pain, pruritus and significant aesthetic impairment. The aetiology of keloid formation is multifactorial, encompassing genetic predispositions, dysregulated inflammation and aberrant mechanical forces. Despite advances in therapeutic modalities, current clinical management strategies, such as silicone gel sheets, intralesional corticosteroids, surgical excision and adjuvant radiotherapy, often yield variable efficacy. With recurrence rates frequently exceeding 50% following monotherapy, preventing recurrence remains a major clinical challenge. This review comprehensively examines the mechanobiology of keloid formation, exploring how physical tension and extracellular matrix stiffness dictate disease progression. A central focus is the mechanosensory-immune axis, which perpetuates a vicious, self-reinforcing mechanics-inflammation-fibrosis feedback loop. We systematically decipher the key signalling cascades responsible for this mechanotransduction, specifically highlighting the transforming growth factor-β/Sma- and Mad-related protein network, integrin-focal adhesion kinase (FAK)-mediated signalling, intracellular calcium flux and the critical Hippo-Yes-associated protein (YAP)/PDZ-binding motif pathway. Furthermore, the role of the mechanosensitive ion channel Piezo1 and the convergence of mechanical and immunological signals via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) axis are evaluated in depth. By elucidating these complex networks, we identify promising, mechanism-informed therapeutic avenues, including FAK, YAP and JAK inhibitors. We highlight the paradigm-shifting potential of targeting both membrane and nuclear mechanics, intracellular mechanical memory, to explain and curb the clinical intractability of keloids. Translating these mechanobiological insights into biomarker-stratified clinical trials will drive a critical shift toward precision mechanomedicine, holding profound potential to dismantle mechanical memory, prevent recurrence and improve patients' quality of life.