Peroxisome-derived and liver-specific hydroxyacid oxidase 1-mediated hydrogen peroxide promotes ferroptosis by augmenting peroxisomal ROS

INTRODUCTION: )-generating enzymes, such as hydroxyacid oxidase 1 (HAO1), contribute to ferroptosis, as well as how they function at the molecular level. OBJECTIVES: production in ferroptosis and its impact on liver cancer progression. METHODS: -specific HyPer probe in conjunction with immunofluorescence and flow cytometry. The role of HAO1 in malignant progression was further examined through in vitro and in vivo functional experiments. RESULTS: HAO1 was found to enhance lipid peroxidation in liver cancer cells by boosting reactive oxygen species (ROS) levels within peroxisomes in an enzyme activity-dependent manner. Furthermore, HAO1 downregulated the p-STAT3/SLC7A11/GPX4 pathway, disrupting glutathione synthesis and impeding ROS scavenging, thereby heightening the susceptibility of cancer cells to ferroptosis. Through this dual mechanism, HAO1 synergistically promoted lipid peroxidation, triggering ferroptosis and inhibiting liver cancer cell proliferation and metastasis. Moreover, coenzyme Flavin Mononucleotide (FMN) was shown to augment the tumor-suppressive activity of HAO1. CONCLUSION: Our findings shed light on the key role of HAO1 in the peroxisome-mediated redox regulation of ferroptosis during liver cancer progression, suggesting a potential therapeutic strategy.