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

) 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 clearance, fatty acid oxidation, and fibrotic phenotypes. As a translational supplement, public CKD datasets with a type 2 diabetes mellitus and diabetic kidney disease (DKD) cohort supported ATGL downregulation and its association with renal dysfunction and lipid abnormalities. Moreover, serum ATGL showed moderate DKD discrimination (AUC 0.789, 95% CI 0.716-0.863). Collectively, these findings support a mechanistic link between FPS-responsive SIRT1/FoxO1/ATGL-associated lipophagy regulation and the attenuation of CKD-associated fibrosis.