Zhong Bo, Zhu Qiaozhen, Wei Panmei, Wang Xinying
Department of General Surgery, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Department of Respiratory and Critical Care Medicine, Shenzhen Nanshan People's Hospital, Shenzhen, Guangdong, China.
Biochem Biophys Res Commun. 2025 Sep 8;778:152352. doi: 10.1016/j.bbrc.2025.152352. Epub 2025 Jul 14.
Trimethylamine N-oxide (TMAO) is a metabolite of the intestinal microbiota and is closely associated with the occurrence and development of Non-alcoholic fatty liver disease (NAFLD). Ferroptosis is a novel form of cell death and an important pathological mechanism exacerbating NAFLD. However, whether TMAO can promote ferroptosis and worsen NAFLD, as well as its related mechanisms, has not been studied. We used palmitic acid (PA) to induce HepG2 cell models and a high-fat diet to construct NAFLD animal models in mice. Western blotting, co-immunoprecipitation (CO-IP), and immunofluorescence were used to validate molecular pathways. ELISA was used to assess TMAO, oxidative markers, and biochemical parameters in serum and cell supernatant; HE staining and oil red O staining were used for histopathological examination. Higher levels of TMAO, MDA, and lower levels of SOD and GSH were found in the serum of NAFLD patients. TMAO promotes ferroptosis to accelerate the progression of NAFLD both in vivo and in vitro. At the cellular level, TMAO inhibits OTUB1, possibly weakening its interaction with SLC7A11, thereby promoting ferroptosis. TMAO induces ferroptosis, which accelerates the progression of NAFLD via the OTUB1/SLC7A11 axis. This provides new insights on the role of intestinal microbiota metabolites in the mechanisms of NAFLD.
氧化三甲胺（TMAO）是肠道微生物群的一种代谢产物，与非酒精性脂肪性肝病（NAFLD）的发生发展密切相关。铁死亡是一种新型细胞死亡形式，是加剧NAFLD的重要病理机制。然而，TMAO是否能促进铁死亡并加重NAFLD及其相关机制尚未见研究报道。我们用棕榈酸（PA）诱导HepG2细胞模型，并用高脂饮食构建小鼠NAFLD动物模型。采用蛋白质免疫印迹法、免疫共沉淀（CO-IP）和免疫荧光法验证分子通路。采用酶联免疫吸附测定（ELISA）法评估血清和细胞上清液中的TMAO、氧化标志物和生化参数；采用苏木精-伊红（HE）染色和油红O染色进行组织病理学检查。NAFLD患者血清中TMAO、丙二醛（MDA）水平升高，超氧化物歧化酶（SOD）和谷胱甘肽（GSH）水平降低。TMAO在体内外均能促进铁死亡，加速NAFLD的进展。在细胞水平上，TMAO抑制卵巢肿瘤相关蛋白1（OTUB1），可能削弱其与溶质载体家族7成员11（SLC7A11）的相互作用，从而促进铁死亡。TMAO通过OTUB1/SLC7A11轴诱导铁死亡，加速NAFLD的进展。这为肠道微生物群代谢产物在NAFLD发病机制中的作用提供了新的见解。
