Lipodystrophy and adipose tissue recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is an early phenotype of skin fibrosis, followed by the accumulation of extracellular matrix (ECM). Lipodystrophy syndromes are estimated to affect 1 in 20,000 people and are associated with metabolic comorbidities. Recently, we showed that fibrosis-associated lipodystrophy depended on sustained Wnt signaling, although the mechanism remains unclear. Transcriptomic profiling of mature dermal adipocytes in vivo revealed that Wnt activation downregulated the de novo lipogenesis (DNL) axis enzymes within 48 h. We further found that expression of fatty acid synthase (FASN), a key DNL enzyme, depends on sustained Wnt activation in vitro and in vivo. In a bleomycin model, and in human systemic sclerosis (< 1 year disease duration) and keloids, FASN was significantly downregulated. Notably, inhibition of FASN in mice during reversal of Wnt-induced fibrosis impaired the recovery of DWAT lipid content and ECM architecture. Collectively, these findings demonstrate that acquired lipodystrophy in skin fibrosis is mediated by a previously unrecognized role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis and highlight its potential as a therapeutic target in skin fibrosis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.