Ma Li, Sun Hanbing, Xiang Nian, Xu Qiushi
College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Xinfeng Rd. 5, Daqing, 163319, China.
Sci Rep. 2025 Apr 25;15(1):14516. doi: 10.1038/s41598-025-98044-6.
Hepatic injury induced by many factors play a central role in the pathogenesis of liver diseases. Punicalagin (PUN) is a major antioxidant polyphenolic compound extracted from pomegranates. The aim of this study was to investigate the potential role of PUN on liver injury induced by nonalcoholic steatohepatitis (NASH). Therefore, the effects and mechanistic action of PUN on NASH mouse model induced by choline-deficient, L-amino acid- defined, high-fat (CDAAH) diet were investigated in vivo. Wild-type or nuclear erythroid 2-related factor 2 (Nrf2) KO mice were fed with CDAAH diet to induce NASH and then treated with PUN (100, 300 or 500 mg kg day) by gavage for 12 weeks. Blood and liver samples were collected to assess liver function, oxidative stress, inflammation, and autophagy pathological status. The results showed that 300 mg/kg PUN was the optimal concentration for relieving hepatic injury in NASH, characterized by decreased activities of serum alanine transaminase, aspartate aminotransferase, and liver lactate dehydrogenase activity and histopathological structural damage, and showed a hepatoprotective effect against NASH. PUN significantly reduced the level of liver inflammation and Txnip-NLRP3 signaling pathway in NASH mice. PUN reduced oxidative stress by reducing liver malondialdehyde levels and the accumulation of reactive oxygen species (ROS) and increasing liver superoxide dismutase and glutathione peroxidase activity. PUN may also attenuate oxidative stress and induce autophagy through the p62/Nrf2 and AMPK/mTOR/ULK1 pathway. More importantly, we found that these protective effects of PUN were attributed to enhanced antioxidant, anti-inflammatory and autophagy activity, which was mediated by the activation of the Nrf2 pathway using Nrf2 KO mice. In summary, the present results indicate that PUN successfully relieved NASH-induced liver damage by upregulating Nrf2 signaling and autophagy.
多种因素所致的肝损伤在肝脏疾病发病机制中起核心作用。石榴皮素（PUN）是从石榴中提取的一种主要抗氧化多酚化合物。本研究旨在探讨PUN对非酒精性脂肪性肝炎（NASH）所致肝损伤的潜在作用。因此，在体内研究了PUN对胆碱缺乏、L-氨基酸限定、高脂肪（CDAAH）饮食诱导的NASH小鼠模型的影响及其作用机制。将野生型或核因子E2相关因子2（Nrf2）基因敲除小鼠喂食CDAAH饮食以诱导NASH，然后通过灌胃给予PUN（100、300或500 mg/kg·天），持续12周。采集血液和肝脏样本以评估肝功能、氧化应激、炎症和自噬病理状态。结果表明，300 mg/kg PUN是缓解NASH肝损伤的最佳浓度，其特征为血清丙氨酸转氨酶、天冬氨酸转氨酶活性及肝乳酸脱氢酶活性降低以及组织病理学结构损伤减轻，且对NASH具有肝保护作用。PUN显著降低了NASH小鼠的肝脏炎症水平和Txnip-NLRP3信号通路。PUN通过降低肝脏丙二醛水平和活性氧（ROS）积累以及增加肝脏超氧化物歧化酶和谷胱甘肽过氧化物酶活性来减轻氧化应激。PUN还可能通过p62/Nrf2和AMPK/mTOR/ULK1途径减轻氧化应激并诱导自噬。更重要的是，我们发现PUN的这些保护作用归因于其增强的抗氧化、抗炎和自噬活性，这是通过使用Nrf2基因敲除小鼠激活Nrf2途径介导的。总之，目前的结果表明，PUN通过上调Nrf2信号和自噬成功缓解了NASH诱导的肝损伤。
