Pachymic acid alleviates secondary lymphedema through the modulation of EETs level and the inhibition of lymphatic fibrosis.

OBJECTIVE

This study evaluated the lymphangiogenesis-promoting and antifibrotic effects of PA, a natural component derived from Poria cocos, and to explore its mechanisms to mitigate lymphedema progression.

METHODS

Tubule formation, spheroid sprouting, cell scratch and transwell assays approaches were used to assess the effects of TGF-β1 and PA on LECs tube formation and migratory capacity. A lymphedema tail loop mouse model was constructed, with tail volume measurements, H&E staining, Masson staining, immunofluorescence, and Western blotting to compare fibrosis and lymphatic vessel neogenesis under PA-treated and untreated conditions. RNA sequencing was employed for transcriptomic analysis, while immunofluorescence and Western blotting were used to investigate the role of the AA-EETs-DHETs pathway in PA-mediated lymphatic repair and the associated mitigation of fibrosis.

RESULTS

Functionally, it enhanced LECs tube formation, sprouting, and migration, while reducing collagen III and α-SMA deposition in both TGF-β1-induced fibrosis and mouse models, alleviating the fibrotic microenvironment. Mechanistically, PA exerted its effects by modulating the AA-CYP2C8/CYP2J2-EETs-sEH-DHETs metabolic pathway, thereby increasing EETs level.

CONCLUSIONS

PA promotes lymphangiogenesis and alleviates LECs fibrosis by increasing EETs level, highlighting its potential as a novel therapeutic target for lymphedema.