Using the atherogenic diet model of NAFLD/NASH, this study is the first to demonstrate that 1) induction of NAFLD/NASH markedly and preferentially suppresses hepatic EET biosynthesis and circulating EET levels through suppression of hepatic CYP epoxygenase expression; and, 2) targeted disruption of Ephx2 restores hepatic and systemic EET levels and attenuates NAFLD/NASH-evoked hepatic inflammation and injury. The gene discussed is EPHX2; the disease is metabolic dysfunction-associated steatohepatitis.