Hepatic ischemia/reperfusion injury (IRI) is a majorfactor contributingto the failure of hepatic resection and liver transplantation. Aspart of our ongoing investigation into bioactive compounds derivedfrom fungi, we isolated eight indole alkaloids (1-8) from the endophytic fungus Aspergillus amoenus TJ507. Among these alkaloids, one previously undescribed compound,amoenamide D (1), was identified. The planar structureof 1 was elucidated by extensive spectroscopic analysis,including HRESIMS and NMR spectra. The absolute configuration of 1 was elucidated by using electronic circular dichroism calculations.Notably, in the CoCl2-induced hepatocyte damage model,notoamide Q (3) exhibited significant anti-hypoxia injuryactivity. Furthermore, in a murine hepatic ischemia/reperfusion injury model, treatment with 3 prevents IRI-induced liver damageand hepatocellular apoptosis. Consequently, 3 might serveas a potential lead compound to prevent hepatic ischemia/reperfusioninjury.