Hepatocyte-derived inducible nitric oxide synthase (iNOS) was proved to impart protection against liver ischemia reperfusion (I/R) injury in our prior analysis. However, the mechanism for this hepatoprotection remains incompletely understood. Bone marrow chimeric mice were generated using expression of iNOS in a hepatocyte-selective manner against an iNOS-knockout background. The function of heme oxygenase 1 (HO-1) in iNOS-stimulated hepatoprotection and the molecular mechanisms were explored in vitro and in vivo, respectively. Hepatocyte-derived iNOS conferred protection from I/R injury and anoxia/reoxygenation stimulation. Mechanistically, iNOS activated nuclear factor erythroid 2-related factor 2 (Nrf-2) and subsequently, stimulated the transcription of HO-1. Results from our study led to the conclusion that HO-1 is another potent mediator of iNOS-mediated protection after liver I/R. (C) 2019 Elsevier Inc. All rights reserved.