Role of Bach1 Transcription Factor in the Mechanisms of Cell Death

Involvement of the transcription factor Bach1 in various scenarios of cellular regulation is reviewed herein. To date, the most extensively studied role of Bach1 is that of a repressor of the antioxidant genetic program initiated by the Nrf2 factor. This program counteracts oxidative stress, which triggers both ferroptosis and the intrinsic apoptotic pathway. Bach1 functions unrelated to the suppression of the Nrf2 transcriptional activity have been studied only fragmentarily. Nevertheless, among these, one could distinguish functions that are specific to the particular forms of cell death. A major consequence of such Nrf2-independent effects is, in particular, direct induction of the expression of the glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) by Bach1; this leads to glutathione degradation and inactivation of the glutathione peroxidase 4 - a central enzyme in the ferroptosis mechanism responsible for the reduction of lipid peroxides. Independently of Nrf2, Bach1 also represses expression of the mitochondrial electron transport chain genes and activates expression of the pyruvate dehydrogenase kinase 1 (PDK1) and hexokinase 2 (HK2), thereby shifting cells toward the glycolytic pathway and rendering them more resistant to apoptosis. Furthermore, Bach1 influences expression of the inflammasome genes and modulates pyroptosis. Bach1 also regulates expression of a number of metallothionein genes and influences control of cuproptosis via the regulation of the free intracellular copper levels. Finally, Bach1 could inhibit autophagy through multiple mechanisms. In essence, the role of Bach1 in many processes - with the exception of the Bach1/Nrf2 axis - remains far from fully elucidated, given that the number of identified target genes exceeds 12,000, and the majority of them are regulated indirectly through formation of the specific protein complexes, which often include epigenetic enzymes. Nevertheless, in the context of various diseases - ranging from neurodegeneration to cancer - inhibition of Bach1 is precisely what is required to achieve a therapeutic effect. The review concludes by discussing clinical significance of Bach1 and the prospects for its therapeutic targeting.