Uric Acid Induces Hepatocytes Ferroptosis Through HIF-2α/DMT1-Mediated Iron Overload

Hyperuricemia is associated with liver dysfunction, yet its molecular mechanisms remain unclear. This study investigated high uric acid (HUA)-induced hepatocyte injury using a hyperuricemia mouse model (HUM) and uric acid (UA)-treated L02 cells. HUM exhibited elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and pathological liver changes. Transmission electron microscopy (TEM) confirmed ferroptotic hallmarks, including mitochondrial shrinkage and increased membrane density. UA exposure upregulated NADPH Oxidase 4 (NOX4), increased Reactive Oxygen Species (ROS), and promoted lipid peroxidation (LPO), accompanied by intracellular Fe²⁺ accumulation. Mechanistically, UA increased hypoxia-inducible factor-2α (HIF-2α) expression, subsequently upregulating iron transporters divalent metal transporter 1 (DMT1) and Transferrin Receptor (TFRC). Deferoxamine (DFO) treatment effectively reversed Fe²⁺ overload and alleviated oxidative stress. Notably, pharmacological inhibition or genetic knockdown of HIF-2α specifically suppressed DMT1 upregulation and restored iron homeostasis, while TFRC expression remained unaffected. Blocking the HIF-2α/DMT1 axis significantly reduced LPO and mitochondrial dysfunction. These findings demonstrate that HUA induces hepatocyte Ferroptosis through HIF-2α-mediated DMT1 upregulation, leading to Fe²⁺ overload and mitochondrial impairment. This study identifies the HIF-2α/DMT1 pathway as a key driver of HUA-induced liver injury and a potential therapeutic target.

DMT1; HIF-2α; ferroptosis; hyperuricemia; lipid peroxidation; liver injury.