– Soluble epoxide hydrolase (sEH) PROTAC 1a is a proteolysis-targeting chimera (PROTAC) comprising a cereblon ligand linked to the sEH inhibitor t-TUCB via a linker, promoting selective sEH degradation and inhibiting its hydrolase activity (IC50 = 0.8 nM) significantly more than its phosphatase activity (IC50 = >10,000 nM). This compound preferentially targets cytosolic sEH for lysosomal rather than proteasomal degradation. Furthermore, it mitigates thapsigargin-induced upregulation of phosphorylated inositol-requiring enzyme 1α (IRE1α) and X-box binding protein 1 (XBP1) splicing in HepG2 and 293T cells, thereby reducing endoplasmic reticulum stress.