Lycopene Ameliorates Hepatic Ischemia‐Reperfusion Injury in Rats by Suppressing HRD1 E3 Ubiquitin Ligase to Restore Nrf2 Signaling

Background: Hepatic ischemia‐reperfusion injury (HIRI) is a critical clinical challenge, and lycopene, a natural carotenoid with antioxidant properties, has shown potential in mitigating organ damage. This research evaluated the therapeutic potential and mechanistic basis of lycopene against HIRI utilizing in vivo and in vitro approaches. Methods: A rat HIRI model and AML‐12 cell models (H 2 O 2 ‐induced oxidative stress and hypoxia/reoxygenation [H/R]) were established. Results: Lycopene significantly alleviated HIRI in rats, evidenced by improved hepatic histopathology (HE staining), restored antioxidant enzyme activities (SOD1 and GSH), and reduced proinflammatory cytokines (TNF‐α, IL‐6, and IL‐1β). Notably, HRD1, an E3 ubiquitin ligase, exhibited dynamic temporal expression: In mild HIRI (30 min ischemia/6 h reperfusion), HRD1 initially increased adaptively but declined thereafter, whereas severe ischemia (60 min) caused persistent HRD1 upregulation during reperfusion, exacerbating apoptosis and liver dysfunction. Lycopene treatment normalized HRD1 levels, reducing apoptosis markers (Bax, Cleaved‐Caspase‐3) and enhancing antiapoptotic Bcl‐2. In vitro, lycopene attenuated H 2 O 2 ‐ and H/R‐induced oxidative stress, inflammation, and apoptosis. Mechanistically, genetic manipulation of HRD1 (silencing or overexpression) confirmed that it targets Nrf2, the central regulator of antioxidant defense, for degradation. Lycopene suppressed HRD1‐mediated Nrf2 ubiquitination, thereby stabilizing Nrf2 and activating downstream antioxidant genes (HO‐1 and NQO1). Conclusions: These findings demonstrate that lycopene ameliorates HIRI by modulating the HRD1‐Nrf2 axis, highlighting its therapeutic potential via dual antioxidant and antiapoptotic mechanisms. This study provides novel insights into HRD1’s context‐dependent roles in HIRI and positions lycopene as a promising candidate for clinical translation.