Xie Chunfeng, Jiang Xinyao, Yin Juan, Jiang Runqiu, Zhu Jianyun, Zou Shenshan
Medical School, Nanjing University, Nanjing 210093, China; Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China.
J Hazard Mater. 2025 Apr 5;487:137166. doi: 10.1016/j.jhazmat.2025.137166. Epub 2025 Jan 9.
Bisphenol S (BPS) is a widely detected environmental toxin with the potential to increase the risk of non-alcoholic fatty liver disease (NAFLD). However, the effects of BPS on the progression of high fat diet (HFD)-induced NAFLD remain unclear. This study aimed to explore the role and underlying mechanisms of action of BPS in HFD-induced NAFLD. Our results showed that BPS exposure (50 and 500 μg/kg bodyweight/day) promoted the progression of NAFLD, which was evidenced by increased liver/body weight ratio, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and more and larger lipid droplets in liver tissues. These phenomena were accompanied by abnormal expression levels of fatty acid uptake (Cd36), fatty acid synthesis (Pparγ, Scd-1, and Fasn), fatty acid oxidation (Pparα), and cytokines (TNFα, IL-1β, and IL-6). In vitro and in vivo studies showed that BPS exposure caused hepatic ferroptosis by regulating ferroptosis-related markers (GPX4, xCT, FTH, and ACSL4). Moreover, BPS exposure caused ROS overproduction, mitochondrial dysfunction, lipid peroxidation, and GSH suppression, all of which were restored by ferrostatin-1, a ferroptosis inhibitor. Moreover, BPS significantly upregulated HMGCS2 expression in the hepatocytes and liver tissues. 3-hydroxy-3-methylglutaryl coenzyme A synthetase 2 (HMGCS2) knockdown mitigated the effects of BPS on hepatocytes and reversed the expression of ferroptosis-related markers. Thus, BPS exposure aggravates HFD-induced NAFLD by regulating HMGCS2-mediated ferroptosis. Collectively, our study indicates that BPS exposure at environmentally relevant concentrations may aggravate NAFLD phenotypes under HFD conditions, highlighting the health risks of BPS to the liver.
双酚S（BPS）是一种广泛检测到的环境毒素，有可能增加非酒精性脂肪性肝病（NAFLD）的风险。然而，BPS对高脂饮食（HFD）诱导的NAFLD进展的影响仍不清楚。本研究旨在探讨BPS在HFD诱导的NAFLD中的作用及潜在作用机制。我们的结果表明，BPS暴露（50和500μg/千克体重/天）促进了NAFLD的进展，这通过肝脏/体重比增加、血清丙氨酸转氨酶和天冬氨酸转氨酶水平升高以及肝组织中更多更大的脂滴得以证明。这些现象伴随着脂肪酸摄取（Cd36）、脂肪酸合成（Pparγ、Scd-1和Fasn）、脂肪酸氧化（Pparα）和细胞因子（TNFα、IL-1β和IL-6）的异常表达水平。体外和体内研究表明，BPS暴露通过调节铁死亡相关标志物（GPX4、xCT、FTH和ACSL4）导致肝脏铁死亡。此外，BPS暴露导致活性氧过度产生、线粒体功能障碍、脂质过氧化和谷胱甘肽抑制，所有这些都被铁死亡抑制剂铁抑素-1恢复。此外，BPS显著上调肝细胞和肝组织中HMGCS2的表达。3-羟基-3-甲基戊二酰辅酶A合成酶（HMGCS2）敲低减轻了BPS对肝细胞的影响，并逆转了铁死亡相关标志物的表达。因此，BPS暴露通过调节HMGCS2介导的铁死亡加重了HFD诱导的NAFLD。总体而言，我们的研究表明，在环境相关浓度下暴露于BPS可能会加重HFD条件下的NAFLD表型，突出了BPS对肝脏的健康风险。
