TRPV4 loss of function leads to uninterrupted CYP2E1 activity and protein levels. Blocking CYP2E1-induced redox toxicity improves outcome in NAFLD pathology. TRPV4 blocks CYP2E1 activity by activating NOS3 and NO release. Mechanistically, Kupffer cell induced NO blocks CYP2E1 in a paracrine manner. TRPV4-CYP2E1 axis is a novel pathway in NAFLD pathology.