MEN1 deficiency establishes a selenite-dependent binary switch in ferroptosis

Replication stress is a hallmark of cancer cells, yet the factors determining tolerance remain poorly understood. Genome-wide CRISPR screens for modifiers of replication-stress responses identified loss of the chromatin scaffold gene MEN1 as a resistance factor. We show that MEN1 deficiency suppresses lipid peroxidation and ferroptotic death, enabling survival following treatment with multiple replication stress-inducing agents. Mechanistically, MEN1 loss reduced H3.3 occupancy at ACSL1 regulatory regions and lowered ACSL1 expression, with ACSL1 loss phenocopying replication stress resistance. MEN1- or ACSL1-deficient cells also exhibited reduced levels of SLC7A11 and glutathione, rendering them hypersensitive to GPX4 inhibition under selenite-limiting conditions. Conversely, selenite supplementation preferentially increased GPX4 abundance and converted these cells to a ferroptosis-resistant state independently of SLC7A11. Thus, MEN1 links chromatin regulation to the ferroptotic control of replication stress responses, while selenite availability determines whether MEN1-deficient cells are vulnerable or resistant.