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

Xiang Fang; Tianzheng Xiao; Yongfeng Li; Da Qian; Chaoqi He; Weimin Hong; Liquan Zhu; Danhong Wang; Xuli Meng; Xiaozhen Liu

doi:10.1016/j.intimp.2025.115066

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

Int Immunopharmacol. 2025 Jun 27:162:115066. doi: 10.1016/j.intimp.2025.115066. Online ahead of print.

Authors

Xiang Fang¹, Tianzheng Xiao², Yongfeng Li³, Da Qian⁴, Chaoqi He³, Weimin Hong⁵, Liquan Zhu³, Danhong Wang³, Xuli Meng⁶, Xiaozhen Liu⁷

Affiliations

¹ Jinzhou Medical University, Department of postgraduate education, Jinzhou, Liaoning, 121001, China; Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
² Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China.
³ Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
⁴ Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Department of Burn and Plastic Surgery-Hand Surgery, Changshu Hospital Affiliated to Soochow University, Changshu No. 1 People's Hospital, Changshu, 215500, China.
⁵ Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen, 518001, China.
⁶ Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China. Electronic address: mxlmail@126.com.
⁷ Department of Breast Surgery, General Surgery, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. Electronic address: liuxiaozhenchina@163.com.

PMID: 40580744
DOI: 10.1016/j.intimp.2025.115066

Abstract

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.

Keywords: CYP2C8; CYP2J2; Fibrosis; Lymphangiogenesis; Lymphoedema; Pachymic acid; sEH.