STC-1 improves scar remodeling and is associated with PI3K/AKT signaling and immune modulation

Background: Dysregulation of the wound remodeling phase can lead to excessive scar formation, which may cause functional impairment and aesthetic distress. However, effective strategies to improve tissue repair outcomes remain limited. Stanniocalcin-1 (STC-1), a secreted glycoprotein, has recently attracted attention for its roles in tissue repair and inflammation, yet its involvement in skin scar remodeling remains unknown.

Methods: A combination of clinical sample analysis, in vitro experiments using NIH-3T3 fibroblasts and macrophage co-culture models, RNA Sequencing, and an in vivo murine full-thickness wound model was employed. The effects of recombinant STC-1 protein and STC-1 overexpression were evaluated on fibroblast function, extracellular matrix (ECM) remodeling, inflammatory response, and scar remodeling.

Results: STC-1 was highly expressed in keloid tissues, primarily in fibroblasts, and its expression was elevated under hypoxic conditions in a HIF-1α-associated manner. In vitro, STC-1 suppressed fibroblast proliferation, migration, and LPS-induced inflammation, while alleviating oxidative stress and mitochondrial dysfunction. STC-1 promoted angiogenesis and M2-like macrophage polarization. In vivo, STC-1 treatment reduced scar size, improved Collagen organization, and modulated immune cell infiltration, accompanied by enhanced PI3K/Akt signaling.

Conclusions: During scar formation, STC-1 modulates fibroblast activity, immune responses, angiogenesis, and ECM remodeling through coordinated regulation of multiple signaling pathways. Collectively, these effects may contribute to STC-1's ability to improve the quality of tissue repair and scar remodeling in vivo. The PI3K/Akt pathway represents one downstream pathway associated with STC-1 activity. However, its efficacy in treating established pathological scars, including keloids, remains to be validated in future studies using more clinically relevant models.