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.