Peroxisome-derived and liver-specific hydroxyacid oxidase 1-mediated hydrogen peroxide promotes ferroptosis by augmenting peroxisomal ROS PMID: 41990971

ADC Targets in Oncology

2026-04-10

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

J Adv Res. 2026 Apr 15:S2090-1232(26)00342-5. doi: 10.1016/j.jare.2026.04.038.

Xintong Peng ¹ , Yanling Zhou ² , Jielin Chen ³ , Zuli Wang ¹ , Xin Peng ³ , Haiyan Wang ¹ , Long Shu ¹ , Na Liu ³ , Yao Long ¹ , Li Linghu ¹ , Zewen Zhang ¹ , Yuanhao Peng ¹ , Yuzheng Zhao ⁴ , Desheng Xiao ⁵ , Ying Shi ⁶ , Shuang Liu ⁷ , Yongguang Tao ⁸

Affiliations

1. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 410078 Changsha, China; National Health Commission Key Laboratory of Carcinogenesis, Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, 410078 Changsha, China.
2. Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008 Changsha, China.
3. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 410078 Changsha, China.
4. Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai 200237, China.
5. Department of Pathology, Xiangya Hospital, Central South University, Changsha Hunan 410008, China. Electronic address: [email protected].
6. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 410078 Changsha, China; National Health Commission Key Laboratory of Carcinogenesis, Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, 410078 Changsha, China. Electronic address: [email protected].
7. Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008 Changsha, China. Electronic address: [email protected].
8. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, 410078 Changsha, China; National Health Commission Key Laboratory of Carcinogenesis, Cancer Research Institute, Xiangya School of Basic Medical Sciences, Central South University, 410078 Changsha, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha Hunan 410008, China; Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan 410031, China. Electronic address: [email protected].

Abstract

Introduction: While peroxisome-associated molecules have been implicated in Ferroptosis, the mechanistic relationship between peroxisomes and Ferroptosis remains poorly understood. Key unresolved questions include whether peroxisomal hydrogen peroxide (H₂O₂)-generating Enzymes, such as hydroxyacid oxidase 1 (HAO1), contribute to Ferroptosis, as well as how they function at the molecular level.

Objectives: This study was designed to investigate the role of HAO1-mediated peroxisomal H₂O₂ production in Ferroptosis and its impact on liver Cancer progression.

Methods: We evaluated HAO1 expression in liver Cancer and its association with patient prognosis using clinical samples and bioinformatic analyses. RNA Sequencing was performed to identify HAO1-regulated biological pathways. Cell viability was measured with a CCK-8 assay, and Ferroptosis was assessed using a C11-BODIPY 581/591 probe, iron assay, and GSH detection. To delineate how HAO1-induced alterations in peroxisomal H₂O₂ affect Ferroptosis, we employed the H₂O₂-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.

Keywords

Ferroptosis; Hydrogen peroxide (H(2)O(2)); Hydroxyacid oxidase 1 (HAO1); Liver cancer; Peroxisome; Reactive oxygen species (ROS).