Fucoidan attenuates renal fibrosis by alleviating tubular ectopic lipid deposition through sirtuin 1/forkhead box protein O1/adipose triglyceride lipase-associated lipophagy

作者：Su J, Liu H, Peng J, Guo Y, Xie H, Dong Z, Liu J, Xu Z, Yu X, Mei J, Hu J, Li F, Zang X, Cai F, Shi Y, Zheng Y, Wang L, Zhang X, Chen W, Liu Q · 发表于：International journal of biological macromolecules · 年份：2026 · DOI：10.1016/j.ijbiomac.2026.154034 · 研究领域：ATGL、Fatty acid oxidation、Fucoidan、Lipophagy、Mitochondrial function、Renal fibrosis

Renal fibrosis, a pathological hallmark of chronic kidney disease (CKD), is associated with dysregulated lipid metabolism, leading to ectopic lipid deposition and tubular lipotoxicity. This highlights the importance of lipophagy, a selective autophagic process that clears lipid droplets. Fucoidan (FPS), a sulfated polysaccharide, has demonstrated renoprotective potential, but whether it alleviates renal fibrosis by restoring lipophagy remains unclear. We investigated this hypothesis using an adenine/Western diet-induced CKD mouse model (FPS, 100 or 200 mg·kg-1·d-1) and TGF-β1/palmitic acid-stimulated HK-2 cells (FPS, 100-400 μg/mL). FPS improved renal function, ameliorated systemic and intrarenal lipid metabolic disturbances, reduced renal lipid deposition, and attenuated tubular injury and interstitial fibrosis. Mechanistically, FPS restored lipophagy-related processes, with increased Beclin1/Atg5/LC3-II and Rab7, reduced p62 accumulation, enhanced ATGL-LC3 and LD-autophagosome/lysosome co-localization, and improved GFP-mRFP-LC3 autophagic flux, accompanied by reduced LD burden. These effects were similar to those of AdipoRon and were attenuated by chloroquine, indicating sensitivity to lysosome-dependent degradation. FPS enhanced fatty acid oxidation and mitochondrial homeostasis. At the signaling level, FPS was associated with SIRT1 upregulation, FoxO1 deacetylation, and ATGL induction, while ATGL silencing diminished improvements in lipophagy-related processes, LD clearan...