Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death

Mg²⁺ is an essential cofactor for numerous enzymes, supporting fundamental cellular processes. The phosphatase of regenerating liver (PRL) protein family, frequently upregulated in cancer, inhibits cyclin M (CNNM) Mg²⁺ efflux transporters. To elucidate the physiological role of PRL in Mg²⁺ homeostasis at the cellular level, we employed combined genetic knockout and knockdown approaches. PRL deletion led to marked reduction of intracellular Mg²⁺ levels and triggered extensive cell death. Transcriptomic analysis revealed activation of the NF-κB pathway, and, accordingly, the genetic deletion of NF-κB p65 subunit abrogated cell death. Similarly, CNNM overexpression triggered intracellular Mg²⁺ decrease, NF-κB activation, and subsequent cell death. Notably, this form of cell death exhibited characteristic morphological features, including actin-driven fiber-like protrusions, distinguishing it from known cell death modalities. Our findings uncover a distinct mode of NF-κB-dependent cell death triggered by intracellular Mg²⁺ decrease.