Glyoxalase-1 Inhibition Leads to Ferroptosis Induction in Lung Cancer Cells: A Dual Mechanism of Action of Hydroxamic Acids Derived from Cysteine.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. In this study, three hydroxamic acids derived from L-cysteine are synthesized to explore their biological dual effect as Glyoxalase 1 (Glo-1) inhibitors and ferroptosis inducers. Among the synthesized derivates, compound 2 exhibited the highest inhibitory potency against Glo-1 and is the most potent compound against nonsmall cell lung cancer cell lines. For this compound, an increase in intracellular reactive oxygen species (ROS), depletion of intracellular reduced glutathione (GSH) levels, and induced morphological changes is observed that correspond to ferroptosis. Furthermore, these effects are reversed by Liproxstatin-1, a potent and selective ferroptosis inhibitor. Acute and subacute toxicological assays in mice showed mild toxicity (LD50 > 2000 mg kg-1) and moderate organ damage. These in vitro and in vivo findings suggest that ferroptosis induction may serve as a side effect of Glo-1 inhibition, making compound 2 a promising lead for further development and optimization.