Harnessing the Therapeutic Potential of the Nrf2/Bach1 Signaling Pathway in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although a complex interplay of multiple environmental and genetic factors has been implicated, the etiology of neuronal death in PD remains unresolved. Various mechanisms of neuronal degeneration in PD have been proposed, including oxidative stress, mitochondrial dysfunction, neuroinflammation, α-synuclein proteostasis, disruption of calcium homeostasis, and other cell death pathways. While many drugs individually targeting these pathways have shown promise in preclinical PD models, this promise has not yet translated into neuroprotective therapies in human PD. This has consequently spurred efforts to identify alternative targets with multipronged therapeutic approaches. A promising therapeutic target that could modulate multiple etiological pathways involves drug-induced activation of a coordinated genetic program regulated by the transcription factor, nuclear factor E2-related factor 2 (Nrf2). Nrf2 regulates the transcription of over 250 genes, creating a multifaceted network that integrates cellular activities by expressing cytoprotective genes, promoting the resolution of inflammation, restoring redox and protein homeostasis, stimulating energy metabolism, and facilitating repair. However, FDA-approved electrophilic Nrf2 activators cause irreversible alkylation of cysteine residues in various cellular proteins resulting in side effects. We propose that the transcriptional repressor of BTB and CNC homology 1 (Bach1), which antagonizes Nrf2, could serve as a promising complementary target for the activation of both Nrf2-dependent and Nrf2-independent neuroprotective pathways. This review presents the current knowledge on the Nrf2/Bach1 signaling pathway, its role in various cellular processes, and the benefits of simultaneously inhibiting Bach1 and stabilizing Nrf2 using non-electrophilic small molecules as a novel therapeutic approach for PD.

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors

“…Considering that the main difference between the Keap1–Nrf2 ETGE interaction and the Keap1–Nrf2 DLGex interaction lies in the P6 subpocket, highlighting the P6 subpocket in drug design might hold enormous promise for the development of Keap1–Nrf2 inhibitors with better selectivity. , In addition, targeting the β-TrCP–Nrf2 pathway has been considered as an unexplored alternative to develop Nrf2 activators with higher target selectivity. ,, Recently, the first β-TrCP - Nrf2 PPI inhibitor has been successfully discovered, which represents a new direction for the future exploitation of safe and potent Nrf2 activators . Mounting evidence suggests that pharmacologic inhibition of BTB and CNC homology 1 (Bach1), a physiological repressor of Nrf2, also represents a promising approach to activate the Nrf2–ARE pathway without involving the electrophilic modification of cellular proteins. , In this regard, BACH1 inhibitors have opened the door for a new class of nonelectrophilic Nrf2 activators. , It is noteworthy that glycogen synthase kinase-3β (GSK-3β) can phosphorylate Nrf2, stimulating its association with β-TrCP and precipitating Nrf2 ubiquitination. , Therefore, GSK-3β inhibitors offer additional ways to activate Nrf2 without electrophilicity concerns. − More attention should be devoted to these areas. Furthermore, Nrf2 hyperactivation has been reported to be tightly related to the development of some other diseases, including but not limited to cancers, − bone hypoplasia, hydronephrosis, and aging acceleration .…”

“…145 Mounting evidence suggests that pharmacologic inhibition of BTB and CNC homology 1 (Bach1), a physiological repressor of Nrf2, also represents a promising approach to activate the Nrf2−ARE pathway without involving the electrophilic modification of cellular proteins. 146,147 In this regard, BACH1 inhibitors have opened the door for a new class of nonelectrophilic Nrf2 activators. 148,149 It is noteworthy that glycogen synthase kinase-3β (GSK-3β) can phosphorylate Nrf2, stimulating its association with β-TrCP and precipitating Nrf2 ubiquitination.…”

NRF2 and STAT3: friends or foes in carcinogenesis?

“…Basally activated in almost all cellular types, autophagy is particularly important in the survival of cancer cells that are forced to live in condition of shortage of oxygen and nutrients [7]. Moreover, the activation of NRF2 is regulated, through a feed-back mechanism, by Batch1, a transcriptional repressor of NRF2 activated by NRF2 itself [8].…”

Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives

“…However, the Nrf2-driven program has a feedback regulation through the transcriptional repressor Bric-a-brac-Tramtrack-Broad (BTB) and cap "n" collar (CNC) homolog 1 (Bach1), which is an Nrf2 target gene and inhibits transcription of a large number of both Nrf2-dependent and Nrf2independent genes. [39,40] Thus, Bach1 activation and inhibition processes are directly implicated in ferroptosis. [41] A recent study showed that Bach1 ablation can protect against ferroptosis in a myocardial infarction model.…”

“…There is a clear understanding that Nrf2 activation and Bach1 inhibition properties in one drug make a “mutually beneficial” combination for treating neurodegenerative disorders with perturbed Nrf2/Bach1 signaling. [ 40,52 ]…”