Nrf2-mediated epigenetic priming of osmoprotective genes enhances cellular adaptation to hyperosmotic stress

Hyperosmotic stress triggers a complex adaptive response that enables cells to maintain homeostasis and survive osmotic perturbations. However, the molecular mechanisms that coordinate transcriptional and epigenetic programs in response to osmotic stress remain poorly defined. Here, through an unbiased chemical screen, we identify activation of nuclear factor erythroid 2 - related factor 2 (Nrf2) as a potent enhancer of cell survival under hyperosmotic stress. Mechanistically, Nrf2 does not function as a sustained transcriptional activator of osmoprotective genes during stress. Instead, Nrf2 establishes a primed chromatin state prior to osmotic challenge, characterized by increased enrichment of activation-associated histone modifications at osmoprotective loci. This epigenetic priming enables enhanced recruitment of NFAT5 upon hyperosmotic stimulation, thereby amplifying osmoprotective gene transcription. Disruption of Nrf2 abolishes chromatin activation, NFAT5 binding, and transcriptional induction of osmoprotective genes, whereas pharmacological Nrf2 activation restores these processes and improves cell survival. In a model of dehydration-induced hyperosmotic stress, renal cell death was markedly increased in Nrf2-deficient mice, while Nrf2 activation promoted the expression of osmoprotective genes and conferred tissue protection. Together, our findings identify Nrf2 as an epigenetic priming factor that licenses NFAT5 - dependent transcription under hyperosmotic stress, revealing a previously unrecognized chromatin-based mechanism that enhances cellular adaptation to osmotic challenges.