{"title":"番茄红素通过抑制HRD1 E3泛素连接酶恢复Nrf2信号通路改善大鼠肝缺血再灌注损伤","authors":"Li Li, Hui Zhang, Yuchao Sun","doi":"10.1155/jfbc/6651066","DOIUrl":null,"url":null,"abstract":"<p><b>Background:</b> 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.</p><p><b>Methods:</b> A rat HIRI model and AML-12 cell models (H<sub>2</sub>O<sub>2</sub>-induced oxidative stress and hypoxia/reoxygenation [H/R]) were established.</p><p><b>Results:</b> 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<sub>2</sub>O<sub>2</sub>- 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).</p><p><b>Conclusions:</b> 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.</p>","PeriodicalId":15802,"journal":{"name":"Journal of Food Biochemistry","volume":"2025 1","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/jfbc/6651066","citationCount":"0","resultStr":"{\"title\":\"Lycopene Ameliorates Hepatic Ischemia-Reperfusion Injury in Rats by Suppressing HRD1 E3 Ubiquitin Ligase to Restore Nrf2 Signaling\",\"authors\":\"Li Li, Hui Zhang, Yuchao Sun\",\"doi\":\"10.1155/jfbc/6651066\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>Background:</b> 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.</p><p><b>Methods:</b> A rat HIRI model and AML-12 cell models (H<sub>2</sub>O<sub>2</sub>-induced oxidative stress and hypoxia/reoxygenation [H/R]) were established.</p><p><b>Results:</b> 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<sub>2</sub>O<sub>2</sub>- 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).</p><p><b>Conclusions:</b> 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.</p>\",\"PeriodicalId\":15802,\"journal\":{\"name\":\"Journal of Food Biochemistry\",\"volume\":\"2025 1\",\"pages\":\"\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1155/jfbc/6651066\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Food Biochemistry\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/jfbc/6651066\",\"RegionNum\":2,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Food Biochemistry","FirstCategoryId":"97","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/jfbc/6651066","RegionNum":2,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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 (H2O2-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 H2O2- 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.
期刊介绍：
The Journal of Food Biochemistry publishes fully peer-reviewed original research and review papers on the effects of handling, storage, and processing on the biochemical aspects of food tissues, systems, and bioactive compounds in the diet.
Researchers in food science, food technology, biochemistry, and nutrition, particularly based in academia and industry, will find much of great use and interest in the journal. Coverage includes:
-Biochemistry of postharvest/postmortem and processing problems
-Enzyme chemistry and technology
-Membrane biology and chemistry
-Cell biology
-Biophysics
-Genetic expression
-Pharmacological properties of food ingredients with an emphasis on the content of bioactive ingredients in foods
Examples of topics covered in recently-published papers on two topics of current wide interest, nutraceuticals/functional foods and postharvest/postmortem, include the following:
-Bioactive compounds found in foods, such as chocolate and herbs, as they affect serum cholesterol, diabetes, hypertension, and heart disease
-The mechanism of the ripening process in fruit
-The biogenesis of flavor precursors in meat
-How biochemical changes in farm-raised fish are affecting processing and edible quality
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