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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\u2013lipid 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.<\/jats:p>","DOI":"10.3390\/md23060228","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:29:36Z","timestamp":1748338176000},"page":"228","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chondroitin Sulfate as a Lysosomal Enhancer Attenuates Lipid-Driven Inflammation via Lipophagy and Mitophagy"],"prefix":"10.3390","volume":"23","author":[{"given":"Ting","family":"Sun","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Lv","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huarong","family":"Shao","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Wang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou Advanced Research Institute for New Materials, Peking University, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixue","family":"Ling","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China"},{"name":"National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/nrgastro.2016.3","article-title":"Management of NAFLD: A stage-based approach","volume":"13","author":"Rinella","year":"2016","journal-title":"Nat. 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