Soluble epoxide hydrolase (sEH) inhibition has been shown multiple beneficial effects against brain injuries of Intracerebral hemorrhage (ICH). However, the underlying mechanism of its neuroprotective effects after ICH has not been explained fully. Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be implicated in the secondary injuries after ICH. In this study, We examined whether sEH inhibition can alleviate brain injuries of ICH through inhibiting ferroptosis. Expression of several markers for ferroptosis was observed in the peri-hematomal brain tissues in mice after ICH. lip-1, a ferroptosis inhibitor, alleviated iron accumulation, lipid peroxidation and the secondary damages post-ICH in mice model. Intraperitoneal injection of 1-Trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl)urea (TPPU), a highly selective sEH inhibitor, could inhibit ferroptosis and alleviate brain damages in ICH mice. Furthermore, RNA-sequencing was applied to explore the potential regulatory mechanism underlying the effects of TPPU in ferroptosis after ICH. C-C chemokine ligand 5 (CCL5) may be the key factor by which TPPU regulated ferroptosis after ICH since CCL5 antagonist could mimic the effects of TPPU and CCL5 reversed the inhibitive effect of TPPU on ferroptosis and the neuroprotective effects of TPPU on secondary damage after ICH. Taken together, these data indicate that ferroptosis is a key pathological feature of ICH and Soluble epoxide hydrolase inhibitor can exert neuroprotective effect by preventing ferroptosis after ICH.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.