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Renal lipotoxicity and chronic inflammation form a self\u2010perpetuating cycle driving DKD, yet multitarget interventions remain underexplored. We hypothesized that simultaneous inhibition of ANGPTL3 and IL\u201033, two key regulators of lipid metabolism and the inflammatory\u2010fibrotic axis, would ameliorate DKD, and that integrating both antagonistic activities into a single bifunctional molecule offers translational advantages. We engineered a bifunctional fusion protein, FD03\u2010sST2, comprising an anti\u2010ANGPTL3 nanobody fused to the IL\u201033 decoy receptor sST2. In high\u2010fat diet\u2010fed db\/db mice, FD03\u2010sST2 significantly improved renal function (ACR, BUN, urine volume), reduced serum\/hepatic lipids, and attenuated renal lipid accumulation. Mechanistically, it suppressed renal inflammation via NF\u2010\u03baB\/NLRP3 inhibition and ameliorated fibrosis by suppressing the IL\u201033\/ST2\/ILC2 axis (reducing renal IL\u201033\/GATA3 signals and inhibiting IL\u201033\u2010induced profibrotic factors from ILC2s). Transcriptomic and metabolomic analyses confirmed attenuation of DKD\u2010associated dysregulation. This study identifies a DKD cascade wherein lipotoxicity triggers IL\u201033 release, amplifying injury through inflammation and fibrosis. By targeting ANGPTL3 and IL\u201033 simultaneously, FD03\u2010sST2 interrupts this vicious cycle at two nodes\u2014improving lipid metabolism while suppressing downstream inflammatory and fibrotic signaling\u2014providing an integrated alternative to separate biologics.<\/jats:p>","DOI":"10.1002\/advs.75756","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:39:30Z","timestamp":1779197970000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting ANGPTL3 and IL\u201033\/ST2 Ameliorates Diabetic Kidney Disease by Reducing Lipotoxicity, Alleviating Inflammation and Inhibiting Fibrosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhuojin","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences and Shanghai Engineering Research Center of Immunotherapeutics Qidong\u2010Fudan Innovative Institute of Medical Sciences Fudan University  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