2025 · Sahu — Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer
Super-Abstract
The Nrf2 transcription factor is the cell's master antioxidant switch — when Nrf2 functions correctly, it defends against cancer-driving oxidative damage; when mutated, it can paradoxically protect tumour cells from therapy. This review explains how molecular hydrogen activates the Nrf2 pathway and where this dual role creates both opportunities and complications for cancer biology. (Biochimica et Biophysica Acta — Molecular Basis of Disease, 2025.)
Commentary
Nrf2 (nuclear factor erythroid 2-related factor 2) is encoded by the NFE2L2 gene and controls the expression of a battery of antioxidant and cytoprotective enzymes (SOD, glutathione, catalase). Under normal conditions, the Keap1-Cul3 E3 ubiquitin ligase complex tags Nrf2 for degradation. Oxidative stress disrupts this complex, allowing Nrf2 to accumulate in the nucleus and switch on defensive gene programmes. This review details the structural domains of Nrf2 (Neh1–7), the conformational changes in Keap1 triggered by ROS, and how specific mutations in ETGE/DLG motifs decouple Nrf2 from Keap1 control — making it constitutively active in many cancers. The H₂-relevant finding is mechanistically interesting: the authors describe evidence that H₂ activates Nrf2 by oxidising iron porphyrin (acting as an electrophile) which then interacts with a cysteine residue in Keap1, triggering the conformational change that releases Nrf2. This is a proposed mechanism — the evidence is largely in-vitro and the precise target is still under investigation.
Key quotes
- „To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway.“ — H₂'s proposed cytoprotective role through Nrf2 pathway activation
- „molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.“ — the specific molecular mechanism proposed for H₂-mediated Nrf2 activation
- „Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer.“ — the upstream pathological cascade that Nrf2 activation is meant to counter
Our assessment
This is a mechanistic review on Nrf2 biology, mutations, and cancer — H₂ appears as one Nrf2-activating agent among many discussed. The proposed mechanism (iron porphyrin oxidation → Keap1 cysteine interaction) is based on in-vitro and computational data and has not been confirmed in human studies. Importantly, Nrf2's dual role — tumour suppressor in normal cells, tumour promoter in constitutively-active mutant cancers — means that broad Nrf2 activation is not without risk in oncological contexts. This nuance is implied by the paper's focus on cancer-promoting Nrf2 mutations but could be stated more explicitly. Readers interested specifically in H₂ should treat the mechanistic claims as hypothesis-generating, not established.
Study design
- Type: mechanistic narrative review · n: n/a (literature synthesis; primary focus on Nrf2 pathway biology and cancer mutations) · H₂ delivery: not specified (H₂ discussed mechanistically, no specific delivery method or dosing cited for human application)
- Result: Nrf2 pathway fully characterised (domain structure, Keap1 interaction, ubiquitin-proteasome regulation); Nrf2-activating role of H₂ proposed via iron porphyrin electrophile → Keap1 cysteine; cancer-associated NFE2L2 mutations reviewed; translational implications discussed
Abstract
Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1-7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.
Source & links
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