Sun Ting, Lv Huimin, Shao Huarong, Zhang Xiuhua, Wang Anqi, Zhang Wei, Liu Fei, Ling Peixue
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Engineering Research Center for Sugar and Sugar Complex, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Key Laboratory of Carbohydrate and Glycoconjugate Drug, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China.
Mar Drugs. 2025 May 27;23(6):228. doi: 10.3390/md23060228.
Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal-lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development.
非酒精性脂肪性肝炎（NASH）是一种以脂质蓄积和慢性炎症为特征的进行性肝脏疾病，缺乏针对其多因素发病机制的有效治疗方法。本研究调查了海洋来源的硫酸软骨素（CS）作为一种能够调节NASH中脂质代谢、氧化应激和炎症的多细胞器调节剂。通过采用亚细胞成像和细胞器特异性标记技术，我们证明CS可恢复NASH模型中的溶酶体酸化，通过溶酶体-脂滴融合减少脂滴。同时，CS上调动力相关蛋白1（DRP1），驱动线粒体末端裂变以在空间上隔离用于线粒体自噬的活性氧（ROS）片段，从而降低ROS水平。值得注意的是，使用氯喹或巴弗洛霉素A1对溶酶体活性进行药理学抑制消除了CS的治疗效果，证实溶酶体酸化是一个必要前提。总的来说，这些发现揭示了CS作为NASH治疗剂的潜力，并为其保护作用的亚细胞机制提供了关键见解，从而为未来的研究和治疗开发奠定了基础。
