Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling

Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, proliferation and apoptosis to maintain cellular homeostasis. It is not understood i...

Celý popis

Uložené v:
Podrobná bibliografia
Vydané v:Toxicology (Amsterdam) Ročník 519; s. 154284
Hlavní autori: Sharma, Raju Prasad, Loonstra-Wolters, Liesanne, ter Braak, Bas, Niemeijer, Marije, White, Andrew, van de Water, Bob, Middleton, Alistair M., Beltman, Joost B.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Ireland Elsevier B.V 01.01.2026
Predmet:
Chemical exposure
Computer Simulation
Emergency
Hep G2 Cells
Hepatotoxicity
Humans
Models, Biological
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nonlinear mixed effect modeling
NRF2
Oxidoreductases Acting on Sulfur Group Donors - genetics
Oxidoreductases Acting on Sulfur Group Donors - metabolism
Repeated exposure
SRXN1
Repeated exposure
Chemical exposure
NRF2
SRXN1
Hepatotoxicity
Nonlinear mixed effect modeling
ISSN:0300-483X, 1879-3185, 1879-3185
On-line prístup:Získať plný text
Tagy: Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
Popis
Shrnutí:Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, proliferation and apoptosis to maintain cellular homeostasis. It is not understood in detail how the NRF2 program acquires its flexibility with respect to regulation of its downstream targets. Various NRF2 binding partners and cofactors specific to ARE genes are involved in this regulation, and are potentially condition-specific (e.g., type of stressor) and dependent on non-canonical signaling pathways (i.e., crosstalk). Here, we explored the quantitative relationship between NRF2 and sulfiredoxin 1 (SRXN1), a bona fide key NRF2 target gene. We developed a semi-mechanistic mathematical model based on time course experimental data of NRF2 and SRXN1 protein expression in HepG2 cells following single or repeated exposure to NRF2 activating soft electrophiles (sulforaphane, andrographolide, ethacrynic acid or CDDO-me) at a wide concentration range. We showed that a nonlinear mixed effect modeling approach with partially hierarchical parameters accurately captures the observed experimental dynamics. Our analysis highlights that NRF2 requires a cofactor or post-translational modification to regulate its activity as a transcription factor. Moreover, this modulation of the transcription factor activity of NRF2 is time-, compound- and exposure scenario specific. We conclude that a complete understanding of NRF2-mediated ARE genes activation requires detailed dynamic information on NRF2 binding partners and cofactors.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0300-483X
1879-3185
1879-3185
DOI:10.1016/j.tox.2025.154284