A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells

While it is well established that the KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative stress, this cytoprotective function of NRF2 could become deleterious to the host if it confers survival onto irreparably damaged cells. In this regard, we have found that in diseased states, NRF2 promotes the transcriptional activation of a specific subset of the senescence-associated secretory phenotype (SASP) gene program, which we have named the NRF2-induced secretory phenotype (NISP). In two models of hepatic disease using Pten::Keap1 and Keap1::Atg7 double knockout mice, we found that the NISP functions in the liver to recruit CCR2 expressing monocytes, which function as immune system effector cells to directly remove the damaged cells. Through activation of this immune surveillance pathway, in non-transformed cells, NRF2 functions as a tumour suppressor to mitigate the long-term survival of damaged cells which otherwise would be detrimental for host survival. This pathway represents the final stage of the oxidative stress response, as it allows cells to be safely removed if the macromolecular damage caused by the original stressor is so extensive that it is beyond the repair capacity of the cell.