Abstract Most cysteine residues are believed to require a reduced state for activity and their oxidation by reactive oxygen species (ROS) is traditionally viewed as damaging to proteins. However, it stands that some cysteines that must be oxidized for protein function, yet their identity remains largely unknown. To answer this question, we lowered ROS levels in 55 lung cancer cell lines and analyzed the cellular consequences using cysteine-focused chemical proteomics paired with functional CRISPR screens. This integrated approach revealed hundreds of impacted cysteines required for proliferation. We focused on NDUFA10•C253 in mitochondrial complex I, which we find exists in a more oxidized state in some human brain metastases. This cysteine is dynamically regulated by antioxidant pathways and its oxidation is required for complex I stability and supports metastasis to the brain. Collectively, we demarcate oxidized cysteines essential for cell fitness and disease states including metastasis. Citation Format: Maolin Ge. Cysteine oxidation is required for brain metastasis in lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4731.
Maolin Ge (Fri,) studied this question.