Aakaash Duggal

Background: Keloids are benign, dermal fibroproliferative growths characterized by excessive collagen accumulation that actively invades beyond original wound margins.¹ They disproportionately affect individuals with darker skin pigmentation (Fitzpatrick skin types IV-VI) and preferentially develop in anatomical areas subjected to high mechanical skin tension, such as the chest and shoulders.¹ Diagnosed clinically, these lesions carry a poor prognosis for spontaneous regression and exhibit a 70-100% recurrence rate following standard surgical excision.² The core pathology is driven by keloid fibroblasts that display a tumor-like phenotype, driven by dysfunctional mechanotransduction and altered metabolism.³⁻⁵ Currently, there is a critical lack of targeted molecular therapies capable of preventing mechanically-induced recurrence without disrupting healthy tissue.²

Objective: In this narrative review, we explored the molecular drivers of keloid pathogenesis—specifically focusing on the Piezo1/YAP mechanotransduction axis and PI3K/AKT metabolic reprogramming—to evaluate the efficacy of targeted, dual-inhibition therapies in promoting scarless regeneration.

Search Methods: An online search of the PubMed database was conducted for primary literature published between 2020 and 2025. Search strategies incorporated Medical Subject Headings (MeSH) terms and text keywords, including “keloid”, “mechanotransduction”, “YAP”, “Piezo1”, “PI3K/AKT”, and “aerobic glycolysis,” to identify high-yield mechanistic studies, in vitro cell lines, and relevant in vivo translation models.

Results: Research demonstrates that keloid fibroblasts possess inherently dysfunctional mechanosensors, maintaining a consistently high, locked-in baseline of active nuclear YAP even in soft extracellular environments.⁴ Single-cell transcriptomics identified the mechanosensitive ion channel Piezo1 as highly enriched in pathological keloids, acting as the primary trigger that translates physical skin stretch into a calcium flux to activate downstream YAP pathways.³ Concurrently, keloid fibroblasts undergo profound metabolic reprogramming via the PI3K/AKT pathway, shifting to rapid aerobic glycolysis (the Warburg effect) to fuel pathological expansion and resist apoptosis.⁵ Mechanistic studies show that inhibiting PI3K/AKT starves these cells of metabolic fuel, triggering significant apoptosis (15.19%).⁵ Crucially, bidirectional cross-talk protects these concurrent pathways, necessitating a dual-inhibition approach.⁵ In vivo xenograft models revealed that pharmacological co-inhibition of YAP (via Verteporfin) and Piezo1 (via GsMTx4) successfully blocked mechanically-induced profibrotic activation, significantly reduced absolute keloid volume, and normalized the pathological Type I to Type III collagen ratio.³ Furthermore, while evaluated in foundational murine wound models, targeted inhibition of this pathway fundamentally shifted the biological response from fibrotic scarring to true wound regeneration, restoring normal extracellular matrix ultrastructure and secondary skin appendages.⁶

Conclusions: The aggressive recurrence of keloids is sustained by a dual system of Piezo1/YAP-mediated mechanical tension and PI3K/AKT-mediated metabolic reprogramming.³⁻⁵ Shifting from reactive surgical excision to proactive, perioperative localized delivery of dual-inhibitor hydrogels can chemically neutralize these cellular engines. By utilizing localized delivery, clinicians can minimize the risk of systemic toxicity, overcome cellular apoptosis resistance, and offer a paradigm-shifting strategy for achieving true scarless wound healing. Ultimately, targeting these mechanometabolic intersections provides a critical translational bridge for the parent disciplines of dermatological surgery and biomaterial engineering, redefining the clinical approach to pathological cutaneous fibrosis.

Works Cited:

1. Limandjaja GC, Niessen FB, Scheper RJ, Gibbs S. The keloid disorder: heterogeneity, histopathology, mechanisms and models. Front Cell Dev Biol. 2020;8:360. doi:10.3389/fcell.2020.00360
2. Ogawa R. The most current algorithms for the treatment of keloids and hypertrophic scars. Plast Reconstr Surg. 2022;149(1):79e-94e. doi:10.1097/PRS.0000000000008667
3. Liao C, Wang P, Zeng Q, et al. Piezo1-mediated calcium flux transfers mechanosignal to Yes-associated protein to stimulate matrix production in keloid. J Invest Dermatol. 2025;145(11):2869-2881. doi:10.1016/j.jid.2025.03.039
4. Deng Z, Subilia M, Chin IL, et al. Keloid fibroblasts have elevated and dysfunctional mechanotransduction signaling that is independent of TGF-β. J Dermatol Sci. 2021;104(1):11-20. doi:10.1016/j.jdermsci.2021.09.002
5. Wang Q, Yang X, Ma J, et al. PI3K/AKT pathway promotes keloid fibroblasts proliferation by enhancing glycolysis under hypoxia. Wound Repair Regen. 2023;31(2):139-155. doi:10.1111/wrr.13067
6. Mascharak S, des Jardins-Park HE, Davitt MF, et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science. 2021;372(6540):eaba2374. doi:10.1126/science.aba2374