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...

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Veröffentlicht in:	Toxicology (Amsterdam) Jg. 519; S. 154284
Hauptverfasser:	Sharma, Raju Prasad, Loonstra-Wolters, Liesanne, ter Braak, Bas, Niemeijer, Marije, White, Andrew, van de Water, Bob, Middleton, Alistair M., Beltman, Joost B.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Ireland Elsevier B.V 01.01.2026
Schlagworte:	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
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Abstract	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.
AbstractList	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.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. 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. AbstractNuclear 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.
ArticleNumber	154284
Author	Loonstra-Wolters, Liesanne White, Andrew Beltman, Joost B. ter Braak, Bas Sharma, Raju Prasad Middleton, Alistair M. van de Water, Bob Niemeijer, Marije
Author_xml	– sequence: 1 givenname: Raju Prasad surname: Sharma fullname: Sharma, Raju Prasad organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands – sequence: 2 givenname: Liesanne surname: Loonstra-Wolters fullname: Loonstra-Wolters, Liesanne organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands – sequence: 3 givenname: Bas surname: ter Braak fullname: ter Braak, Bas organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands – sequence: 4 givenname: Marije surname: Niemeijer fullname: Niemeijer, Marije organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands – sequence: 5 givenname: Andrew surname: White fullname: White, Andrew organization: Safety, Environmental and Regulatory Science, Unilever, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, UK – sequence: 6 givenname: Bob surname: van de Water fullname: van de Water, Bob organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands – sequence: 7 givenname: Alistair M. surname: Middleton fullname: Middleton, Alistair M. organization: Safety, Environmental and Regulatory Science, Unilever, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, UK – sequence: 8 givenname: Joost B. orcidid: 0000-0001-9215-3087 surname: Beltman fullname: Beltman, Joost B. email: j.b.beltman@lacdr.leidenuniv.nl organization: Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, Leiden 2333 CC, the Netherlands
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Keywords	Repeated exposure Chemical exposure NRF2 SRXN1 Hepatotoxicity Nonlinear mixed effect modeling
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Snippet	Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control... AbstractNuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which...
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SubjectTerms	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
Title	Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling
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