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This study identifies angiopoietin\u2010like protein 4 (ANGPTL4) as a potential regulator of podocyte lipophagy in DKD. In renal biopsies from patients with DKD, ANGPTL4 is upregulated in podocytes, and its expression is associated with greater proteinuria and more rapid renal function decline. In immortalized human podocytes, exposure to high glucose and palmitic acid (HGPA) increases both intracellular and secreted ANGPTL4, impairs autophagic flux, and promotes lipid droplet accumulation. Mechanistically, ANGPTL4 overexpression reduces TFEB nuclear localization, increases lysosomal pH, and decreases cathepsin B and lysosomal acid lipase activities, consistent with impaired terminal lysosomal lipid degradation. Conversely, ANGPTL4 knockdown restores autophagic and lysosomal programs under HGPA conditions. Recombinant human N\u2010terminal ANGPTL4 fragment reproduces several TFEB\u2010localization, lysosomal, and lipophagic defects, whereas extracellular neutralization partially reverses these changes. Expression of constitutively active TFEB\u2010S211A restores lysosomal function and lipid clearance and attenuates profibrotic remodeling. Collectively, these findings support an ANGPTL4\u2013TFEB\u2010associated lysosome\u2013lipophagy pathway linking diabetic metabolic stress to defective lipid clearance and podocyte injury.<\/jats:p>","DOI":"10.1002\/advs.76771","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:14:09Z","timestamp":1785154449000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ANGPTL4 Exacerbates Renal Injury in Diabetic Kidney Disease by Impairing Podocyte Lipophagy via Compromised Lysosomal Degradative Function"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7544-9150","authenticated-orcid":false,"given":"Xiaojing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Nephrology China\u2010Japan Friendship Hospital  Beijing 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