Iron is essential for life. Many enzymes require iron for appropriate function. However, dysregulation of intracellular iron homeostasis produces excessive reactive oxygen species (ROS) via the Fenton reaction and causes devastating effects on cells, leading to ferroptosis, an iron-dependent cell death. In order to protect against harmful effects, the intracellular system regulates cellular iron levels through iron regulatory mechanisms, including hepcidin–ferroportin, divalent metal transporter 1 (DMT1)–transferrin, and ferritin–nuclear receptor coactivator 4 (NCOA4). During iron deficiency, DMT1–transferrin and ferritin–NCOA4 systems increase intracellular iron levels via endosomes and ferritinophagy, respectively. In contrast, repleting extracellular iron promotes cellular iron absorption through the hepcidin–ferroportin axis. These processes are regulated by the iron-regulatory protein (IRP)/iron-responsive element (IRE) system and nuclear factor erythroid 2-related factor 2 (Nrf2). Meanwhile, excessive ROS also promotes neuroinflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB forms inflammasomes, inhibits silent information regulator 2-related enzyme 1 (SIRT1), and induces pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β). Furthermore, 4-hydroxy-2,3-trans-nonenal (4-HNE), the end-product of ferroptosis, promotes the inflammatory response by producing amyloid-beta (Aβ) fibrils and neurofibrillary tangles in Alzheimer’s disease, and alpha-synuclein aggregation in Parkinson’s disease. This interplay shows that intracellular iron homeostasis is vital to maintain inflammatory homeostasis. Here, we review the role of iron homeostasis in inflammation based on recent findings.

Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body’s antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, metastasis, and cell survival. Cancer cells exhibit enhanced ATP production and high ROS levels, which allow them to maintain elevated proliferation through metabolic reprograming. In order to prevent further ROS generation, cancer cells rely on more glycolysis to produce ATP and on the pentose phosphate pathway to provide NADPH. Pro-oxidant therapy can induce more ROS generation beyond the physiologic thresholds in cancer cells. Alternatively, antioxidant therapy can protect normal cells by activating cell survival signaling cascades, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in response to radio- and chemotherapeutic drugs. Nrf2 is a key regulator that protects cells from oxidative stress. Under normal conditions, Nrf2 is tightly bound to Keap1 and is ubiquitinated and degraded by the proteasome. However, under oxidative stress, or when treated with Nrf2 activators, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors. This cascade results in the expression of detoxifying enzymes, including NADH-quinone oxidoreductase 1 (NQO1) and heme oxygenase 1. NQO1 and cytochrome b5 reductase can neutralize ROS in the plasma membrane and induce a high NAD⁺/NADH ratio, which then activates SIRT1 and mitochondrial bioenergetics. NQO1 can also stabilize the tumor suppressor p53. Given their roles in cancer pathogenesis, redox homeostasis and the metabolic shift from glycolysis to oxidative phosphorylation (through activation of Nrf2 and NQO1) seem to be good targets for cancer therapy. Therefore, Nrf2 modulation and NQO1 stimulation could be important therapeutic targets for cancer prevention and treatment.

Recent findings suggest that NADH-dependent enzymes of the plasma membrane redox system (PMRS) play roles in the maintenance of cell bioenergetics and oxidative state. Neurons and tumor cells exhibit differential vulnerability to oxidative and metabolic stress, with important implications for the development of therapeutic interventions that promote either cell survival (neurons) or death (cancer cells). Here we used human neuroblastoma cells with low or high levels of the PMRS enzyme NADH-quinone oxidoreductase 1 (NQO1) to investigate how the PMRS modulates mitochondrial functions and cell survival. Cells with elevated NQO1 levels exhibited higher levels of oxygen consumption and ATP production, and lower production of reactive oxygen species. Cells overexpressing NQO1 were more resistant to being damaged by the mitochondrial toxins rotenone and antimycin A, and exhibited less oxidative/nitrative damage and less apoptotic cell death. Cells with basal levels of NQO1 resulted in increased oxidative damage to proteins and cellular vulnerability to mitochondrial toxins. Thus, mitochondrial functions are enhanced and oxidative stress is reduced as a result of elevated PMRS activity, enabling cells to maintain redox homeostasis under conditions of metabolic and energetic stress. These findings suggest that NQO1 is a potential target for the development of therapeutic agents for either preventing neuronal degeneration or promoting the death of neural tumor cells.