Hara Emika, Ohshima Kanami, Takimoto Mio, Bai Yidan, Hirata Mai, Zeng Wen, Uomoto Suzuka, Todoroki Mai, Kobayashi Mio, Kozono Takuma, Kigata Tetsuhito, Shibutani Makoto, Yoshida Toshinori
Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Cooperative Division of Veterinary Sciences, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
Int J Mol Sci. 2025 Mar 17;26(6):2709. doi: 10.3390/ijms26062709.
Flutamide (FL), a non-steroidal drug used for its antiandrogenic, anticancer, and disrupting endocrine properties, induces mitochondrial toxicity and drug metabolism enzymes and promotes hepatocarcinogenesis. The inhibition of mitophagy, leading to the accumulation of damaged mitochondria, is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of FL in high-fat diet (HFD)-induced non-obese steatosis rats, categorized into four groups: basal diet (BD), BD + FL, HFD, and HFD + FL. The FL exacerbated HFD-induced steatosis and marginally increased preneoplastic lesions. To analyze hepatic preneoplastic lesions, we divided them into clusters based on the expression ratios of the mitophagy regulators LC3 and AMBRA1. The expression rates of LC3 and AMBRA1 in these precancerous lesions were classified into three clusters using -means clustering. The HFD group exhibited an increased ratio of mitophagy inhibition clusters, as indicated by decreased LC3 and increased AMBRA1 levels in background hepatocytes and preneoplastic lesions. FL counteracted HFD-mediated mitophagy inhibition, as indicated by increased LC3 and decreased AMBRA1 levels in background hepatocytes. Our clustering analysis revealed that FL-induced mitophagy induction relied on Parkin expression. The present study underscores the significance of cluster analysis in understanding the role of mitophagy within small preneoplastic lesions and suggests that FL may potentially exacerbate NAFLD-associated hepatocarcinogenesis by affecting mitophagy.
氟他胺（FL）是一种非甾体类药物，具有抗雄激素、抗癌和破坏内分泌的特性，可诱导线粒体毒性和药物代谢酶，并促进肝癌发生。线粒体自噬的抑制会导致受损线粒体的积累，这与非酒精性脂肪性肝病（NAFLD）的发病机制有关。在本研究中，我们调查了FL对高脂饮食（HFD）诱导的非肥胖性脂肪变性大鼠的影响，将其分为四组：基础饮食（BD）组、BD + FL组、HFD组和HFD + FL组。FL加剧了HFD诱导的脂肪变性，并略微增加了癌前病变。为了分析肝脏癌前病变，我们根据线粒体自噬调节因子LC3和AMBRA1的表达比率将它们分为不同的簇。使用均值聚类法将这些癌前病变中LC3和AMBRA1的表达率分为三个簇。HFD组显示出线粒体自噬抑制簇的比例增加，背景肝细胞和癌前病变中LC3水平降低和AMBRA1水平升高表明了这一点。FL抵消了HFD介导的线粒体自噬抑制，背景肝细胞中LC3水平升高和AMBRA1水平降低表明了这一点。我们的聚类分析表明，FL诱导的线粒体自噬诱导依赖于帕金蛋白的表达。本研究强调了聚类分析在理解小癌前病变中线粒体自噬作用方面的重要性，并表明FL可能通过影响线粒体自噬而潜在地加剧NAFLD相关的肝癌发生。
