Circ_0039857: A Key Player in Combating Immune Disorders and Ferroptosis in High-Glucose-induced HK-2 Cells and Diabetic Kidney Disease Mice

Diabetic kidney disease (DKD) is a microvascular complication associated with diabetes. Circ_0039857 has been shown to exert regulatory functions in various human diseases. This research aimed to elucidate the role and mechanism of circ_0039857 in DKD. Our findings revealed that both circ_0039857 and miR-4739 expressions were decreased in DKD, while PON1 levels were elevated. Functionally, circ_0039857 overexpression repressed immune disorders and ferroptosis in HG-induced HK-2 cells. Mechanistically, circ_000888 was bound to miR-4739, and miR-4739 was bound to PON1. Meanwhile, the effects of circ_0039857 overexpression on immune disorder and ferroptosis in HG-induced HK-2 cells were abolished after miR-4739 mimic or si-PON1 co-transfection, revealing the key regulatory function of circ_0039857/miR-4739/PON1 axis in DKD. Furthermore, circ_0039857 repressed DKD progression in vivo, mainly by reducing the proliferation of renal mesangial cells and renal collagen deposition in DKD mice. Also, circ_0039857 reduced immune disorders and ferroptosis in in vivo model of DKD. In summary, circ_0039857 overexpression inhibited immune disorders and ferroptosis by targeting miR-4739/PON1, thus alleviating DKD.