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3.3 The role of ferroptosis in the pathogenesis of DN Diabetes prevalence is rising globally, with diabetic nephropathy (DN)affecting 20%50% of diabeticsbeing the leading cause of ESRD ( 3.3.1 System Xc GSHGPX4 axis imbalance GPX4, the central suppressor of ferroptosis, detoxifies lipid peroxides (PLOOH) with GSH as a cofactor in the pathogenesis of DN ( subunit) and GPX4, with reduced GSH and elevated lipid peroxides under high glucose (HG) ( 3.3.2 Iron overload under high glucose promotes ROS generation and triggers ferroptosis HG disrupts iron homeostasis: upregulated TFR1 (iron uptake) and downregulated FTH1 (iron storage) lead to LIP expansion ( 2+ triggers Fenton reactions, generating ROS and lipid peroxides