The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the cellular antioxidant response, controlling the expression of genes that counteract oxidative and electrophilic stresses. Many pathological conditions are linked to imbalances in redox homeostasis, illustrating the important role of antioxidant defense systems in preventing the pathogenic effects associated with the accumulation of reactive species. In particular, it is becoming increasingly apparent that the accumulation of lipid peroxides has an important role in driving the pathogenesis of multiple disease states. A key example of this is the recent discovery of a novel form of cell death termed ferroptosis. Ferroptosis is an iron-dependent, lipid peroxidation-driven cell death cascade that has become a key target in the development of anti-cancer therapies, as well as the prevention of neurodegenerative and cardiovascular diseases. In this review, we will provide a brief overview of lipid peroxidation, as well as key components involved in the ferroptotic cascade. We will also highlight the role of the NRF2 signaling pathway in mediating lipid peroxidation and ferroptosis, focusing on established NRF2 target genes that mitigate these pathways, as well as the relevance of the NRF2-lipid peroxidation-ferroptosis axis in disease.

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Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10μg/L, but levels>50-1000μg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure.

SUMMARY While the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo . Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.

The metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway is increasingly linked to aging and age-associated disease. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular redox homeostasis, and energy production. Aberrant kynurenine metabolism is observed during normal aging and has been implicated in a range of age-associated pathologies, including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. In previous work, we and others identified three genes-kynu-1, tdo-2, and acsd-1-encoding kynurenine pathway enzymes for which decreasing expression extends lifespan in invertebrate models. Here we report that knockdown of haao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated decline in health in Caenorhabditis elegans. This lifespan extension is mediated by increased physiological levels of the HAAO substrate 3-hydroxyanthranilic acid (3HAA). 3HAA increases resistance to oxidative stress during aging by directly degrading hydrogen peroxide and activating the Nrf2/SKN-1 oxidative stress response. Aging mice fed a diet supplemented with 3HAA are similarly long-lived. Our results identify HAAO and 3HAA as novel therapeutic targets for age-associated disease. This works provides a foundation for more detailed examination of the molecular mechanisms underlying the benefits of 3HAA, and how these mechanisms interact with other interventions both within and beyond the kynurenine pathway. We anticipate that these findings will bolster growing interest in developing pharmacological strategies to target tryptophan metabolism to improve health aging.