The PI3K/AKT/mTOR pathway in scar remodeling and keloid formation: mechanisms and therapeutic perspectives
Jing Liu, Junfei Yan, Shengbin Qi, Jie Zhang, Xin Zhang, Yaping Zhao
Abstract
Keloids and hypertrophic scars (HTS) represent aberrant wound healing characterized by excessive fibroblast activity and extracellular matrix accumulation. The PI3K/AKT/mTOR signaling pathway is vital in regulating these processes, promoting fibroblast proliferation, survival, and collagen synthesis. Dysregulation of this pathway, driven by genetic mutations, post-transcriptional modulation, and upstream signaling, contributes significantly to the pathogenesis of pathological scarring. This review collects current knowledge on the molecular mechanisms underlying PI3K/AKT/mTOR activation in keloids and HTS, highlighting the roles of key regulators such as PTEN, NEDD4, and non-coding RNAs. It also evaluates therapeutic strategies targeting this axis, including small-molecule inhibitors, natural compounds, and emerging delivery platforms. Targeting PI3K/AKT/mTOR offers a compelling avenue for developing effective, mechanism-based keloid and hypertrophic scarring treatments. The PI3K/AKT/mTOR signaling axis is central to these cellular mechanisms, which drive fibroblast proliferation, survival, myofibroblast transdifferentiation, and metabolic reprogramming (including suppressed autophagy and enhanced glycolysis.