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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302563 | GEO | 2025/07/19

REPOSITORIES: GEO

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	GSE302563_processed_data.xlsx	Xlsx

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Project description:Lymphedema (LD) is characterized by the accumulation of protein-rich interstitial fluid, lipids and a significant inflammatory cell infiltrate in the limb. It causes a significant morbidity and is a common disabling disease affecting more than 150 million people worldwide, however there is no yet curative treatment. In this study, we found that LD tissues from patients exhibit inflamed gene expression profile compared to their normal arm. This was next confirmed by a lipidomic analysis that revealed severe decrease in arachidonic acid-derived lipid mediators generated by the 15-lipoxygenase (15-LO) in lymphedematous arms. Using a mouse model of lymphedema, we reproduced the etiology of the human pathology including the loss of specialized pro-resolving lipid mediators that play essential role in resolution of inflammation. This was associated with a lack of nonlymphoid PPAR-positive regulatory T cells (Treg) recruitment in the injured limb adipose tissue. Importantly, we identified the lymphatic endothelial 15-LO as responsible for the chemoattraction and survival of this Treg subpopulation. These results were confirmed by an aggravation of LD and degradation of the lymphatic network in an original transgenic mouse model in which ALOX15 gene has been selectively deleted in the lymphatic system (ALOX15lecKO). Importantly, this phenotype was rescued by the injection of ALOX15-expressing lentivectors. These results provide evidence that lymphatic 15-LO may represent a novel therapeutic target for LD by serving as a mediator of nonlymphoid Treg cell population invasion into lymphedematous adipose tissue to resolve inflammation. Experimental workflow: To broadly identify gene expression signatures associated to secondary LD, we performed bulk-RNA sequencing on dermolipectomy tissue samples from women who developed LD after breast cancer. Four patient biopsies (normal arm and LD arm in each patient) were studied and the differential expression analysis (DEseq) followed by a protein-coding RNA profiling.

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

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