Inhibition of soluble epoxide hydrolase ameliorates renal injury in IgA nephropathy by restoring epoxyeicosatrienoic acids

  • iScience. 2026 Jun 1;29(6):116200. doi: 10.1016/j.isci.2026.116200.
Hou-Hua Yin  1  2  3 ,  Xian Fu  1  2  3 ,  Qing Qiao  4 ,  Enqin Yang  2  3 ,  Ya-Nan Liu  2  3 ,  Ying Bai  2  3 ,  Ling Huang  2  3 ,  Yi-Yu Chen  2  3 ,  Zhu-Ying Huang  2  3 ,  Di-Chun Yu  2  3 ,  Ping Dai  2  3 ,  Qing-Jin Pan  2  3 ,  Yi-Wen Meng  2  3 ,  Si-Yi Yin  2  3 ,  Xiao Liu  2  3 ,  Shenyou Nie  2  3 ,  Bing-Qing Deng  4 ,  Yi He  2  3 ,  Jun-Yan Liu  1  2  3
Affiliations
  • 1. CNTTI of College of Pharmacy & Anesthesia Department of the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
  • 2. Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (CNTTI), Ministry of Education, Chongqing 400016, China.
  • 3. Department of Chemical Biology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 4. The Department of Nephrology, the Fourth Affiliated Hospital of Soochow University, Suzhou 215125, China.
PMID: 42256278 DOI: 10.1016/j.isci.2026.116200
Abstract

Immunoglobulin A (IgA) nephropathy (IgAN) is a major cause of end-stage renal disease with limited therapies. Altered lipid metabolism is implicated in chronic kidney disease, but its role in IgAN is unclear. Plasma oxylipin profiling and renal single-cell RNA Sequencing (scRNA-seq) revealed reduced epoxyeicosatrienoic acids (EETs) and increased soluble Epoxide Hydrolase (sEH) in IgAN. Two sEH inhibitors, t-AUCB and macamide, reduced proteinuria, improved renal function, attenuated IgA deposition, and restored EET levels. Mechanistically, sEH overexpression activated NF-κB (p65 phosphorylation) and upregulated TNF-α, IL- 6, and IL-1β; its inhibitors reversed these effects. In human mesangial cells, 14(15)-EET suppressed IgA1-induced NF-κB and cytokine expression. Thus, dysregulated lipid peroxidation drives renal inflammation via the NF-κB-cytokine axis in IgAN. sEH inhibition stabilizes EETs and preserves renal function, highlighting the sEH-EET axis as a promising therapeutic target.

Keywords
molecular biology; nephrology; small molecule; therapeutics.
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