Epigenetic reprogramming via EZH2 inhibition rescues fibroadipose pathogenesis in secondary lymphedema through activating PPARγ signaling

Secondary lymphedema, a progressive disorder characterized by pathological fibroadipose tissue accumulation, is a common problem after cancer treatment and orthopedic surgery. It remains a therapeutic enigma due to its self-perpetuating fibrotic cascade and lack of disease-modifying therapies.Human skin tissue was collected from lymphedema patients and normal controls. Histological/immunofluorescence staining and RNA sequencing were performed. Fibrous tissue was observed in lymphedema samples. RNA sequencing and gene set enrichment analysis (GSEA) revealed significant downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling in lymphedema tissue. Human subcutaneous tissue from ISL stage III lymphedema patients (n = 5) and from normal controls (n = 3) were collected for RNA-seq.