Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal

Abstract

Ferroptosis is triggered by a chain of intracellular labile iron‐dependent peroxidation of cell membrane phospholipids. Ferroptosis is important not only as a cause of ischaemic and neurodegenerative diseases but also as a mechanism of cancer suppression, and a better understanding of its regulatory mechanism is required. It has become clear that ferroptosis is finely controlled by two oxidative stress‐responsive transcription factors, NRF2 (NF‐E2‐related factor 2) and BACH1 (BTB and CNC homology 1). NRF2 and BACH1 inhibit and promote ferroptosis, respectively, by activating or suppressing the expression of genes in the major regulatory pathways of ferroptosis: intracellular labile iron metabolism, the GSH (glutathione) ‐GPX4 (glutathione peroxidase 4) pathway and the FSP1 (ferroptosis suppressor protein 1)‐CoQ (coenzyme Q) pathway. In addition to this, NRF2 and BACH1 control ferroptosis through the regulation of lipid metabolism and cell differentiation. This multifaceted regulation of ferroptosis by NRF2 and BACH1 is considered to have been acquired during the evolution of multicellular organisms, allowing the utilization of ferroptosis for maintaining homeostasis, including cancer suppression. In terms of cell–cell interaction, it has been revealed that ferroptosis has the property of propagating to surrounding cells along with lipid peroxidation. The regulation of ferroptosis by NRF2 and BACH1 and the propagation phenomenon could be used to realize anticancer cell therapy in the future. In this review, these points will be summarized and discussed.

GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

“…One such component is the nuclear factor (erythroid-derived 2)-like-2 (Nrf-2), which controls the expression of Gpx4 in addition to a variety of other antioxidant molecules. Nrf2 activity itself is governed by the regulatory elements BTB and CNC homology 1 or Kelch-like ECH-associated protein 1, each of which are potential therapeutic targets for controlling Gpx4 expression/function ( He et al, 2022 ; Nishizawa et al, 2022 ; Padilla and Lee, 2021 ; Yu and Xiao, 2021 ). It will be important to assess the role of these Gpx4 regulatory factors in host resistance to Mtb in pursuing this general approach for HDT of tuberculosis.…”

JNK signalling regulates self-renewal of proliferative urine-derived renal progenitor cells via inhibition of ferroptosis

“…demonstrated increased expression of HO-1 in renal proximal tubular cells resulted in alleviation of ferroptosis (Adedoyin et al, 2018). Moreover, HO-1 is a marker for active NRF2, a transcription factor activating the expression of several genes encoding anti-ferroptotic proteins, including GPX4 (Nishizawa et al, 2022).…”

The Possible Connection of Two Dual Function Processes: The Relationship of Ferroptosis and the JNK Pathway

“…Since NRF2 induces the expression of genes whose products are involved in the detoxification of reactive oxygen species, it probably counteracts the ferroptotic pathway. Furthermore, NRF2 can inhibit ferroptosis by altering the expression of multiple genes in the regulation of labile iron, the synthesis of GSH and lipid hydroperoxides reduction by GPX4, and the FSP1-dependent CoQ system [ 43 ]. All of these observations may suggest that the inhibition of JNK by JNK-IN-8 or SP600125 might have caused the inhibition of NRF2 too and maintained the elevated ROS and lipid ROS levels due to longer exposure to the ferroptosis inducers, sensitizing the HT-1080 to ferroptosis and deepening its cancer cell toxicity ( Figure 1 and Figure 2 ).…”