Advances in targeted treatment of ferroptosis in diabetic kidney disease with SGLT2 inhibitors

Ferroptosis, an iron-dependent form of cell death, has recently gained attention in the file of diabetic kidney disease (DKD). It is characterized by the iron-catalyzed lipid peroxide accumulations, distinguishing it from the traditional forms of cell death, such as apoptosis and necrosis. Ferroptosis, which is closely associated with oxidative stress, may contribute to the progression of DKD. The discovery of ferroptosis provides new insights into DKD pathogenesis and may represent a novel therapeutic target. Recent research has shown that Sodium - glucose cotransporter 2 inhibitors (SGLT2i) may exert their kidney protecting effects by modulating ferroptosis-related pathways, thereby indirectly influencing the occurrence of ferroptosis. Therefore, this review systematically elucidates the molecular mechanisms by which SGLT2i target and inhibit ferroptosis in DKD. These mechanisms primarily involve: stabilizing the expression of SLC7A11 and SLC40A1 to restore glutathione synthesis and iron metabolic homeostasis; activating the AMPK/NRF2 axis to enhance antioxidant defense capacity; modulating the BHB-CaMKK2 axis to alleviate mitochondrial oxidative stress and lipid peroxidation via enhanced ketogenesis; down-regulating the HIF-1α/HO-1 pathway to mitigate oxidative injury associated with iron overload; and inhibiting the TGF-β/Smad signaling pathway to attenuate ferroptosis in renal tubular epithelial cells and renal fibrosis. Furthermore, SGLT2i may also indirectly modulate the ferroptosis via intervention in the MAPK and PKC-related pathway. In summary, SGLT2i inhibit ferroptosis through multiple pathways, thereby providing novel theoretical foundations and therapeutic dimensions for the early intervention of DKD. Further basic and clinical research is warranted to clarify the precise regulatory network and long-term clinical benefits in humans.