Targeting angiopoietin-like protein 3 and Interleukin-1β alleviated liver and kidney injury through attenuation of lipotoxicity and normalization of glycolipid metabolism in db/db mice

Objective Concomitant liver and kidney injury is a critical pathological feature of metabolic disorders, but current organ-specific therapies often fail to provide cross-protection. Lipotoxicity is a core mechanism linking damage in both organs. Therefore, this study aimed to investigate whether simultaneously targeting ANGPTL3 and IL-1β could attenuate lipotoxicity and thereby ameliorate concomitant liver and kidney injury. Methods A novel bispecific antibody (BsAb) targeting both ANGPTL3 and IL-1β was generated and characterized by SDS-PAGE, SEC-HPLC, thermal stability analysis, SPR and in vitro bioassay. Then, its protective effects were subsequently studied in the db/db mouse model and the underlying mechanisms were revealed by biochemical examinations, histopathological analysis, immunofluorescence (IF), ELISA, RNA-seq, Immunohistochemical (IHC). Results Administration of the BsAb in db/db mice effectively improved liver and kidney function with alleviated liver steatosis and inflammation, as well as reduced kidney glomerular injury. Furthermore, the treatment attenuated lipotoxicity in both organs and normalized the glycolipid metabolism including restored hepatic glycogen reserves and enhanced renal utilization of fatty acids. Conclusion The results demonstrate that the anti-ANGPTL3/IL-1β BsAb alleviates concomitant liver and kidney injury in db/db mice by attenuating lipotoxicity and normalizing glycolipid metabolism, which highlights a promising therapeutic approach for addressing multi-organ damage in metabolic disorders.