Targeting ANGPTL3 and IL‐33/ST2 Ameliorates Diabetic Kidney Disease by Reducing Lipotoxicity, Alleviating Inflammation and Inhibiting Fibrosis

ABSTRACT Current therapies for diabetic kidney disease (DKD) targeting hyperglycemia and hypertension fail to halt progression, urging exploration of additional drivers. Renal lipotoxicity and chronic inflammation form a self‐perpetuating cycle driving DKD, yet multitarget interventions remain underexplored. We hypothesized that simultaneous inhibition of ANGPTL3 and IL‐33, two key regulators of lipid metabolism and the inflammatory‐fibrotic 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‐sST2, comprising an anti‐ANGPTL3 nanobody fused to the IL‐33 decoy receptor sST2. In high‐fat diet‐fed db/db mice, FD03‐sST2 significantly improved renal function (ACR, BUN, urine volume), reduced serum/hepatic lipids, and attenuated renal lipid accumulation. Mechanistically, it suppressed renal inflammation via NF‐κB/NLRP3 inhibition and ameliorated fibrosis by suppressing the IL‐33/ST2/ILC2 axis (reducing renal IL‐33/GATA3 signals and inhibiting IL‐33‐induced profibrotic factors from ILC2s). Transcriptomic and metabolomic analyses confirmed attenuation of DKD‐associated dysregulation. This study identifies a DKD cascade wherein lipotoxicity triggers IL‐33 release, amplifying injury through inflammation and fibrosis. By targeting ANGPTL3 and IL‐33 simultaneously, FD03‐sST2 interrupts this vicious cycle at two nodes—improving lipid metabolism while suppressing downstream inflammatory and fibrotic signaling—providing an integrated alternative to separate biologics.