Multi-organ proteomics identifies oxidative stress pathways underlying genetic and pharmacological SGLT2 suppression
6 affiliations
- 1Division of Cardiovascular Sciences, School of Medical Sciences, College of Life Sciences, University of Leicester, Leicester, UK
- 2Division of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK; National Institute for Health and Care Research Biomedical Research Centre Leicester, UK
- 3Division of Respiratory Sciences, College of Life Sciences, University of Leicester, Leicester, UK
- 4Division of Cardiovascular Sciences, School of Medical Sciences, College of Life Sciences, University of Leicester, Leicester, UK; National Institute for Health and Care Research Biomedical Research Centre Leicester, UK
- 5Division of Cardiovascular Sciences, School of Medical Sciences, College of Life Sciences, University of Leicester, Leicester, UK; Leicester Van Geest Multi-OMICS Facility, University of Leicester, Leicester, UK
- 6National Institute for Health and Care Research Biomedical Research Centre Leicester, UK; Diabetes Research Centre, College of Life Sciences, University of Leicester, Leicester General Hospital, Leicester, UK
Abstract
Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide clinical benefits beyond glycaemic control, although the underlying systemic mechanisms remain incompletely understood. Methods : We performed proteomic profiling across eight metabolically relevant tissues and plasma in high-fat diet-fed mice with either genetic deletion (SGLT2 −/− ) or pharmacological inhibition (dapagliflozin) of SGLT2. Differentially expressed proteins were analysed using Gene Ontology, KEGG pathway enrichment, and integrative clustering. Cross-species comparison was performed using plasma and skeletal-muscle proteomic datasets from participants with type 2 diabetes treated with dapagliflozin. Results: Both genetic and pharmacological SGLT2 inhibition induced widespread tissue-specific proteomic remodelling, particularly in liver, adrenal glands, and adipose tissue. Enrichment analyses consistently identified oxidative stress, mitochondrial function, and metabolic pathways as dominant processes. Shared protein signatures across conditions were strongly linked to reactive oxygen species regulation, mitochondrial respiration, and glutathione metabolism. Tissue-specific analyses revealed divergent responses, including increased oxidative pathways in liver and adrenal tissue, but reduced oxidative signalling in adipose tissue and heart. Cross-species analyses identified overlapping oxidative stress-, mitochondrial- and energy-metabolism pathways in human plasma and skeletal muscle. Conclusions : SGLT2 inhibition induces coordinated multi-organ proteomic remodelling characterised by conserved oxidative stress and mitochondrial signatures, supporting a systemic mechanism underlying the pleiotropic benefits of SGLT2 inhibitors.
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BibTeX
@article{nascimento2026multiorgan,
title = {{Multi-organ proteomics identifies oxidative stress pathways underlying genetic and pharmacological SGLT2 suppression}},
author = {Marta Parente Nascimento and Ilyas Majid and Anu Arthy Murugan Karunagaran and Sophia Ginns and Dorothee Heger and Cian Sutcliffe and Ayesha Roked and John McDonald and Thong Huy Cao and Paulene Quinn and Colleen B. Maxwell and Luke A. Baker and Melanie J. Davies and Donald JL. Jones and Leong L. Ng and Elina Akalestou},
journal = {Redox Biology},
year = {2026},
month = nov,
doi = {10.1016/j.redox.2026.104472},
url = {https://doi.org/10.1016/j.redox.2026.104472},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-organ proteomics identifies oxidative stress pathways underlying genetic and pharmacological SGLT2 suppression
AU - Marta Parente Nascimento
AU - Ilyas Majid
AU - Anu Arthy Murugan Karunagaran
AU - Sophia Ginns
AU - Dorothee Heger
AU - Cian Sutcliffe
AU - Ayesha Roked
AU - John McDonald
AU - Thong Huy Cao
AU - Paulene Quinn
AU - Colleen B. Maxwell
AU - Luke A. Baker
AU - Melanie J. Davies
AU - Donald JL. Jones
AU - Leong L. Ng
AU - Elina Akalestou
PY - 2026
DA - 2026/11/06
JO - Redox Biology
DO - 10.1016/j.redox.2026.104472
UR - https://doi.org/10.1016/j.redox.2026.104472
AB - Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide clinical benefits beyond glycaemic control, although the underlying systemic mechanisms remain incompletely understood. Methods : We performed proteomic profiling across eight metabolically relevant tissues and plasma in high-fat diet-fed mice with either genetic deletion (SGLT2 −/− ) or pharmacological inhibition (dapagliflozin) of SGLT2. Differentially expressed proteins were analysed using Gene Ontology, KEGG pathway enrichment, and integrative clustering. Cross-species comparison was performed using plasma and skeletal-muscle proteomic datasets from participants with type 2 diabetes treated with dapagliflozin. Results: Both genetic and pharmacological SGLT2 inhibition induced widespread tissue-specific proteomic remodelling, particularly in liver, adrenal glands, and adipose tissue. Enrichment analyses consistently identified oxidative stress, mitochondrial function, and metabolic pathways as dominant processes. Shared protein signatures across conditions were strongly linked to reactive oxygen species regulation, mitochondrial respiration, and glutathione metabolism. Tissue-specific analyses revealed divergent responses, including increased oxidative pathways in liver and adrenal tissue, but reduced oxidative signalling in adipose tissue and heart. Cross-species analyses identified overlapping oxidative stress-, mitochondrial- and energy-metabolism pathways in human plasma and skeletal muscle. Conclusions : SGLT2 inhibition induces coordinated multi-organ proteomic remodelling characterised by conserved oxidative stress and mitochondrial signatures, supporting a systemic mechanism underlying the pleiotropic benefits of SGLT2 inhibitors.
SN - 2213-2317
ER -