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

## TL;DR

This study shows that glutathione activates PKM2, linking it to cancer metabolism and ferroptosis, offering a new therapeutic strategy.

## Contribution

GSH is identified as an A-A type allosteric activator of PKM2, revealing a novel regulatory mechanism in cancer metabolism.

## Key findings

- GSH stabilizes PKM2 in its active tetrameric form by binding at the A-A interface.
- Depleting GSH and activating PKM2 enhances ferroptosis and suppresses tumor growth in xenograft models.
- Elevated PKM2 and SLC7A11 levels correlate with poor survival, suggesting their role as potential biomarkers.

## 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.

Glutathione (GSH) defines oxidative balance, but can it directly tune central metabolism? The research reveals that GSH binds and potently activates pyruvate kniase M2 (PKM2), rewiring glycolysis and dictating ferroptosis sensitivity. Combining GSH depletion with PKM2 activation triggers mitochondrial damage and lipid peroxidation, profoundly suppressing tumor growth in vivo. This unexpected vulnerability presents a promising new strategy for cancer therapy.