Angiogenin alleviates lipotoxicity-induced impairment of skin wound healing

Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic stress has been unknown. Here, we demonstrate for the first time that Angiogenin effectively protects against lipotoxicity-induced delayed skin repair. In a cellular lipotoxicity model induced by oleic and palmitic acids (OPA) using human umbilical vein endothelial cells (HUVECs), the levels of Angiogenin decreased in a time- and dose-dependent manner. Meanwhile, a similar reduction was also observed in the skin tissue of high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE)^-/- mice. Restoring Angiogenin levels significantly enhanced endothelial proliferation, migration, and angiogenesis, rescuing OPA-induced impairment. Through RNA-seq and subsequent validations, we provide novel mechanistic insight into Angiogenin's protective action: Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. Critically, we show that the Angiogenin-mediated endothelial rescue is strictly dependent on this Cav1 upregulation. Furthermore, topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE^-/- and high-fat diet/STZ-induced diabetic mice. Collectively, our study unveils a novel Angiogenin-Cav1 axis in endothelial protection, positioning Angiogenin as a promising therapeutic candidate for lipotoxicity-induced impairment of skin wound healing.