The JAK–STAT pathway in keloid pathogenesis: a systematic review with qualitative synthesis

Abstract

Keloid tissues contain inflammatory cells and upregulated pro‐inflammatory cytokines. The Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway mediate cellular responses to these cytokines. We performed a systematic review on the role of the JAK–STAT pathway in keloid pathogenesis and the evidence for JAK–STAT inhibitors in keloid treatment. The search combined the terms (1) keloid and (2) JAK or TYK or STAT and included MeSH terms and synonyms. Two reviewers screened the articles and assessed the full texts on eligibility. Data were collected on the tested drugs and molecules, the type of cells and tissues used in the experiments, and study findings on the association between the JAK–STAT pathway and keloid cells and tissues. A total of twenty preclinical studies were included. Eleven preclinical studies proved that STAT3 expression and phosphorylation are enhanced in keloid tissue and keloid fibroblasts. Thirteen different JAK and/or STAT inhibitors were investigated. Tested drugs inhibited keloid progression as demonstrated by different processes, including reduced collagen production, cell proliferation and migration, increased cell cycle arrest and apoptosis, enhanced antioxidant responses, decreased (paracrine) signalling, and decreased profibrotic gene expression. No clinical studies have been published to date. Preclinical studies indicate a role for the JAK–STAT pathway in keloid pathogenesis and a potential role for JAK–STAT inhibitors in keloid treatment. The effect of these drugs should be further investigated on relevant biomarkers in a human keloid skin model, preferably including immune cells besides keloid fibroblasts and keratinocytes and in clinical studies.

Insights into How Plant-Derived Extracts and Compounds Can Help in the Prevention and Treatment of Keloid Disease: Established and Emerging Therapeutic Targets

“…The JAK/STAT pathway regulates a wide range of cellular functions, such as proliferation, differentiation, migration, apoptosis, etc., in response to various cytokines and other stimuli [56]. Recently, as the importance of the JAK-STAT pathway in the pathogenesis of keloids has been recognized, studies targeting this pathway for keloid treatments are expanding [57,58].…”

JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

“…The results demonstrated that patients achieved durable SVR35 (≥35% spleen volume reduction) and improved TSS50 (≥50% reduction in total symptom score) (Harrison et al, 2022a). Moreover, potential natural products such as plant-derived cucurbitacin I and curcumin analogue ASC-J9 could be used as JAK/STAT inhibitors to treat related diseases (Yin et al, 2023), and the small molecule drugs, which screened from the databases (Dogra et al, 2023), targeting JAK/STAT could also be regarded as treatment strategies for related diseases (various organ fibrosis, etc.) (Liu et al, 2023).…”