摘要It is well established that the synthesis of extracellular matrix(ECM)in mesangial cells is a major determinant of diabetic kidney disease(DKD).Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression.tRF3-lleAAT is a tRNA-derived fragment(tRF)produced by nucleases at tRNA-specific sites,which is differentially expressed in the sera of patients with diabetes mellitus and DKD.In this study we investigated the potential roles of tRFs in DKD.Db/db mice at 12 weeks were adapted as a DKD model.The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-lleAAT and increased ferroptosis and ECM synthesis in the kidney tissues.The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells.We administered ferrostatin-1(1 mg/kg,once every two days,i.p.)to the mice from the age of 12 weeks for 8 weeks,and found that inhibition of the onset of ferroptosis significantly improved renal function,attenuated renal fibrosis and reduced collagen deposition.Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice.Furthermore,we found that the expression of zinc finger protein 281(ZNF281),a downstream target gene of tRF3-IleAAT,was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT.In high glucose-treated mesangial cells,knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis.We demonstrated the targeted binding of tRF3-IleAAT to the 3'UTR of ZNF281.In conclusion,tRF3-IleAAT inhibits ferroptosis by targeting ZNF281,resulting in the mitigation of ECM synthesis in DKD models,suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.