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journal article·2026-01Open access

GSH as an A‐A Type Allosteric Activator of PKM2: Modulating Cancer Cell Homeostasis and Ferroptosis Susceptibility

Tsan‐Jan Chen, Chi‐Jen Lo, Meng‐Jen Wu, Wei Yang Sit, Hsin‐Yu Hsu, Yi‐Cheng Huang, Chien‐Hung Lu, Yu‐Lun Chen, Wei‐Kai Fang, Shan‐Min Yang, Pei‐Lien Chen, Tokuko Haraguchi, Yasushi Hiraoka, Chun‐Yu Lin, Mei‐Ling Cheng, Muh‐Hwa Yang, Hsing‐Jien Kung, Wen‐Ching Wang

Advanced Science· Volume 13· Issue 5
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Abstract

Abstract This study identifies glutathione (GSH) as an endogenous A‐A type allosteric activator of pyruvate kinase M2 (PKM2), stabilizing it in its active tetrameric form through binding at the A‐A interface. This PKM2‐GSH interaction links GSH metabolism to ferroptosis regulation. Transcriptomic analyses across cancers demonstrate strong correlations between GSH, SLC7A11, PKM2, glycolysis, and ferroptosis pathways. By depleting GSH and activating PKM2, ferroptosis is enhanced in PKM2‐dependent cancer models. This approach leads to significant changes in central carbon and lipid metabolism, disrupts mitochondrial function, and drives ferroptotic cell death. The combined treatment markedly suppresses tumor growth in a xenograft model. Elevated PKM2 and SLC7A11 expression levels correlate with poorer survival outcomes, indicating their potential as biomarkers for ferroptosis‐based therapy. The findings demonstrate a dual role for GSH in cellular homeostasis and identify the PKM2‐GSH‐SLC7A11 axis as a therapeutic target for aggressive cancers.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Cancer, Hypoxia, and Metabolism · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Institute of Molecular and Cellular Biology and Department of Life Science National Tsing Hua University Hsinchu 300044 Taiwan

Graduate School of Science Osaka University Toyonaka 560‐0043 Japan

Metabolomics Core Laboratory Healthy Aging Research Center Chang Gung University Taoyuan 333323 Taiwan

Clinical Metabolomics Core Laboratory Chang Gung Memorial Hospital Taoyuan 333423 Taiwan

Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu 300093 Taiwan

Graduate School of Frontier Biosciences Osaka University Suita 565–0871 Japan

Center for Intelligent Drug Systems and Smart Bio‐devices National Yang Ming Chiao Tung University Hsinchu 300093 Taiwan

Cancer and Immunology Research Center National Yang Ming Chiao Tung University Taipei 112304 Taiwan

School of Dentistry Kaohsiung Medical University Kaohsiung 807378 Taiwan

Department of Biomedical Sciences College of Medicine Chang Gung University Taoyuan 333323 Taiwan

Institute of Clinical Medicine National Yang Ming Chiao Tung University Taipei 112304 Taiwan

Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology Taipei Medical University Taipei 110301 Taiwan

Department of Biochemistry and Molecular Medicine Comprehensive Cancer Center University of California Davis, Sacramento CA 95817 USA

Funding

Ministry of Science and Technology · National Health Research Institutes

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