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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.<\/jats:p>","DOI":"10.3389\/fphar.2025.1678953","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T06:34:09Z","timestamp":1764830049000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["The PI3K\/AKT\/mTOR pathway in scar remodeling and keloid formation: mechanisms and therapeutic perspectives"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengbin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3250","DOI":"10.1096\/fj.07-8218com","article-title":"Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis","volume":"21","author":"Aarabi","year":"2007","journal-title":"FASEB J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1586\/17512433.2016.1109443","article-title":"Potential benefits of pentoxifylline on wound healing","volume":"9","author":"Ahmadi","year":"2016","journal-title":"Expert Rev. 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