<scp>STC2</scp> Serves as a Critical Hypoxic Effector in Keloid Pathogenesis by Orchestrating Fibroblasts Activation and <scp>ECM</scp> Remodelling

Abnormal activation of keloid fibroblasts (KFs) within a hypoxic microenvironment is a hallmark of keloid pathogenesis. However, the precise molecular mechanisms by which hypoxia drives fibroblast dysfunction remain insufficiently understood. This study aimed to investigate the role of Stanniocalcin 2 (STC2), a hypoxia-responsive glycoprotein, in modulating keloid fibroblast behaviour under hypoxic conditions and to elucidate its upstream and downstream regulatory networks. We found the expression of STC2 was significantly upregulated in keloid tissues and primary KFs, with expression levels positively correlating with clinical severity, as assessed by the Vancouver Scar Scale. Mechanistically, hypoxia induced STC2 expression via hypoxia-inducible factor-1α. Functional assays revealed that STC2 silencing under hypoxia markedly reduced KF proliferation, migration and extracellular matrix remodelling, as evidenced by downregulation of fibrosis-associated markers including collagen I, α-SMA, MMP2 and MMP9. These inhibitory effects were accompanied by attenuation of ERK and AKT signalling pathway activation. Thus, targeting STC2 disrupts pro-fibrotic signalling and may represent a promising therapeutic strategy for the clinical management of keloid scars by modulating the aberrant hypoxic microenvironment.