Reactive oxygen species-induced lipid peroxidation mediates Wnt-dependent lipodystrophy and associated skin fibrosis

Skin fibrosis is marked by extracellular matrix accumulation and dermal white adipose tissue (DWAT), resulting in tissue stiffening. We show that sustained Wnt activation in mature dermal adipocytes induces lipodystrophy and promotes fibrotic remodeling via oxidative stress. Meta-analysis of early systemic sclerosis skin transcriptomes reveals increased reactive oxygen species (ROS) production and lipid peroxidation. In cultured mouse dermal adipocytes, Wnt activation triggers a robust increase in ROS and lipid peroxidation, which is suppressed by scavengers. In vivo, Wnt activation elevates oxidative stress in DWAT, and N-acetyl-L-cysteine scavenger protects from DWAT lipodystrophy and dermal collagen accumulation. These findings identify a Wnt-ROS-lipid peroxidation axis as a key driver of lipodystrophy and skin fibrosis, highlighting a potential therapeutic target.