Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Nobiletin alleviates alcoholic fatty liver disease by regulating lipid metabolism and oxidative stress via Ephx1 and Sult1a1.
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Zhu Huilin, Zikela Lalai, Wang Dingli, Yu Zhuoli, Zhu Yuzhe, Zhou Hui, Li Xinyao, Wu Yue, Han Qiang
Аннотация
BACKGROUND: Alcoholic fatty liver disease (AFLD) remains a global health burden with limited treatment options. This study investigates nobiletin (NOB), a hexamethoxyflavone, for its potential in AFLD treatment through integrated epidemiological and mechanistic approaches.
OBJECTIVES: This study integrated population-based analysis of dietary flavone intake with experimental investigations to examine the association between flavone intake and AFLD risk and to elucidate the molecular mechanisms underlying the hepatoprotective effects of NOB in AFLD.
METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 data (n=5,027) a nationally representative survey of the U.S. population, to examine the association between dietary flavone intake and AFLD, adjusting for potential confounders. Mechanistic studies employed alcohol-fed C57BL/6J mice with 4-week NOB intervention, followed by transcriptomic and qPCR analyses of hepatic genes. Key findings were validated in vitro.
RESULTS: After adjusting for confounders, 2025 dietary flavone intake was inversely associated with AFLD risk (OR: 0.330; 95% CI: 0.099-0.818). Furthermore, restricted cubic spline analysis showed a linear dose-response relationship. NOB was found to restore dysregulation of lipid metabolism and oxidative stress-related genes and reverse the aberrant expression of 16 genes. Alcohol treatment upregulated the expression of epoxide hydrolase 1 (Ephx1) and sulfotransferase 1A1 (Sult1a1) in the liver and hepatocytes, which positively correlated with hepatic injury markers. In vitro experiments further confirmed the critical role of Ephx1 and Sult1a1 in mediating NOB's protective effects against AFLD.
CONCLUSION: This integrated analysis suggests a potential hepatoprotective role of NOB in AFLD, supported by population-level epidemiological context for flavone intake and mechanistic evidence from experimental models. These findings identify NOB as a promising candidate for further investigation in AFLD-related research.
OBJECTIVES: This study integrated population-based analysis of dietary flavone intake with experimental investigations to examine the association between flavone intake and AFLD risk and to elucidate the molecular mechanisms underlying the hepatoprotective effects of NOB in AFLD.
METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 data (n=5,027) a nationally representative survey of the U.S. population, to examine the association between dietary flavone intake and AFLD, adjusting for potential confounders. Mechanistic studies employed alcohol-fed C57BL/6J mice with 4-week NOB intervention, followed by transcriptomic and qPCR analyses of hepatic genes. Key findings were validated in vitro.
RESULTS: After adjusting for confounders, 2025 dietary flavone intake was inversely associated with AFLD risk (OR: 0.330; 95% CI: 0.099-0.818). Furthermore, restricted cubic spline analysis showed a linear dose-response relationship. NOB was found to restore dysregulation of lipid metabolism and oxidative stress-related genes and reverse the aberrant expression of 16 genes. Alcohol treatment upregulated the expression of epoxide hydrolase 1 (Ephx1) and sulfotransferase 1A1 (Sult1a1) in the liver and hepatocytes, which positively correlated with hepatic injury markers. In vitro experiments further confirmed the critical role of Ephx1 and Sult1a1 in mediating NOB's protective effects against AFLD.
CONCLUSION: This integrated analysis suggests a potential hepatoprotective role of NOB in AFLD, supported by population-level epidemiological context for flavone intake and mechanistic evidence from experimental models. These findings identify NOB as a promising candidate for further investigation in AFLD-related research.