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

TL;DR

High uric acid causes liver cell damage through iron overload and mitochondrial dysfunction, offering a new therapeutic target for liver injury.

Contribution

This study identifies the HIF-2α/DMT1 pathway as a novel mechanism linking hyperuricemia to hepatocyte ferroptosis.

Findings

High uric acid increases HIF-2α and DMT1, leading to iron overload and oxidative stress in hepatocytes.

Blocking the HIF-2α/DMT1 axis reduces lipid peroxidation and mitochondrial dysfunction in liver cells.

Deferoxamine treatment reverses iron overload and oxidative stress caused by uric acid exposure.

Abstract

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.

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