Introduction: Chronic kidney disease (CKD) presents a significant global health challenge, characterized by increased fibrosis and metabolic disturbances. B56δ, a regulatory B subunit of protein phosphatase 2A (PP2A), is known to mediate the activity of PP2Acα in regulating de novo lipid synthesis and the progression of kidney fibrosis. Due to the potential severe toxic side effects associated with targeting PP2Acα directly, the substrate selectivity of the regulatory B subunits makes it a more favorable alternative. Methods: Epirubicin (EPI) was identified as a high-affinity binder to B56δ through screening approaches. Its therapeutic effects were evaluated in a murine model of unilateral ureteral obstruction (UUO) and in TGF-β-stimulated NRK-52E cells. Lipid deposition, fibrotic markers, extracellular matrix accumulation, and cell viability were assessed to determine efficacy and safety. Results: Administration of EPI in UUO mice markedly reduced renal lipid accumulation and attenuated fibrosis progression. In TGF-β-treated NRK-52E cells, EPI significantly decreased lipid droplet formation and extracellular matrix deposition without exerting notable cytotoxic effects. Conclusions: Targeted inhibition of B56δ using EPI represents a promising adjunctive therapeutic strategy for CKD, effectively mitigating lipid dysmetabolism and fibrotic progression while demonstrating a favorable safety profile.
Chen et al. (Fri,) studied this question.