Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production

Sep 21, 2026

Uploaded by Patrick

Glucose and amino acid metabolism are essential for glioblastoma growth, yet targetable metabolic vulnerabilities remain poorly defined. Integrated genomic analysis across 32 human cancers identifies GBM as the highest in cysteine and methionine pathway gene expression. Patient-derived GBM cells treated with FDA-approved N-acetylcysteine show reduced growth and oxygen consumption, intensified by glucose starvation, while normal brain and other cancers respond minimally. Mechanistically, cysteine compounds trigger rapid mitochondrial H2O2 production and reductive stress, modulated by redox pathways and mitochondrial redox enzyme expression, and can induce oxidative stress in mouse brain tumors.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Key findings

Metabolic profiling and targetability in GBM

Effects of cysteine compounds on GBM cells

Mechanism: mitochondrial H2O2 and reductive stress

Modulation by redox enzymes and glutathione pathways

In vivo relevance and therapeutic implications

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production Evan K. Nocha, b,1, Laura Palmab, Isaiah Yimb, Nayah Bullenb, Daniel Barnettc , Alexander Walshc , Bhavneet Bhinderd,e, Elisa Benedettid,e, Jan Krumsiekd,e, Justin Gurvitchb , Sumaiyah Khwajab, Daphne Atlasf, Olivier Elementod,e, and Lewis C. Cantleyg Edited by Karen Vousden, The Francis Crick Institute, London, United Kingdom; received October 17, 2023; accepted December 21, 2023 Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBMxenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM. glioblastoma | reductive stress | cysteine | hydrogen peroxide | mitochondrial metabolism Glioblastoma (GBM) is one of the most lethal human cancers, with a median overall survival of just 14 to 16 mo despite surgical resection, chemotherapy, and radiation (1, 2) . Increased flux through glucose and amino acid metabolic pathways is central to GBM proliferation (3) and is regulated primarily through oncogene-controlled membrane transporters and metabolic enzymes (4–6) . These nutrients facilitate energy production through ATP generation and also protect against oxidative stress through the generation of NADPH (3) . Unlike systemic cancers, GBM is adapted to the nutrient pool available within the central nervous system. Because the brain uses 20% of the body’s glucose (7), GBM cells can access a vast supply of glucose for growth. In these cells, glucose is preferentially used for mitochondrial glucose oxidation, indicating a dependency on mitochondrial-generated ATP production in GBM (8). The excess of certain amino acids, such as glutamate, in the brain also fuels GBM growth by killing surrounding neurons, promoting inflammation, and inducing brain edema (9–13). These studies support the targeting of brain-associated nutrient metabolism in GBM. Cysteine is a sulfur-containing amino acid that is required for glutathione production. Cysteine levels are regulated through a variety of membrane-bound amino acid transporters, including the cystine-glutamate antiporter system Xc − , which plays a critical role in the oxidative stress response in GBM and other cancers (14, 15) . The oxidation and reduction status of intracellular cysteine is also an indicator of the cellular redox status and can control survival from oxidative stress (16) . Likewise, the intracell

FAQs

Which analysis indicates cysteine pathway activity is unusually high in glioblastoma?

Comparing GBM to other human cancers using The Cancer Genome Atlas shows GBM has the highest cysteine and methionine pathway gene expression among 32 cancers.

What does N-acetylcysteine do to glioblastoma cells and how is glucose involved?

N-acetylcysteine reduces GBM cell growth and mitochondrial oxygen consumption, and these effects worsen under glucose starvation.

How do cysteine compounds induce the reported stress in GBM mitochondria?

They rapidly produce mitochondrial hydrogen peroxide, triggering reductive stress, with the effect blocked or reversed by redox-related interventions such as oxidized glutathione, thioredoxin, or redox enzyme overexpression.

Sep 21, 2026

Uploaded by Patrick

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