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

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.