Hepatic Ischemia-reperfusion (I/R) injury, critical challenge in liver surgery and transplantation, exerts a significant impact on the prognosis and survival of patients. Inflammation and cell death play pivotal roles in pathogenesis of hepatic I/R injury. Indoleamine 2, 3-dioxygenase 1 (IDO-1), a key enzyme involved in the kynurenine pathway, has been extensively investigated for its regulatory effects on innate immune responses and cell ferroptosis. However, the precise involvement of IDO-1 in hepatic I/R injury remains unclear.IDO-1 knockout mice were generated to establish a murine model of liver partial warm ischemia and reperfusion, while an in vitro Hypoxia/Reoxygenation (H/R) model was employed to simulate ischemia/reperfusion injury.The involvement of ferroptosis was observed to be involved in hepatic I/R injury, and effective mitigation of liver injury was achieved through the inhibition of ferroptosis. In the context of hepatic I/R injury, up-regulation of IDO-1 was found in macrophages exhibiting prominent M1 polarization and impaired efferocytosis. Deficiency or inhibition of IDO-1 alleviated hepatocytes ferroptosis and M1 polarization induced by hepatic I/R injury, while also enhancing M2 polarization and promoting efferocytosis in macrophages. Furthermore, depletion of macrophages attenuated ferroptosis in hepatocytes induced by hepatic I/R injury.This study highlights the crucial role of IDO-1 activation in macrophages in triggering ferroptosis in hepatocytes during hepatic ischemia-reperfusion injury. Our findings suggest that targeting IDO-1 could be a promising therapeutic strategy for mitigating hepatic I/R injury associated with liver surgery and transplantation.Copyright © 2024 Elsevier B.V. All rights reserved.