Multi-organ proteomics identifies oxidative stress pathways underlying genetic and pharmacological SGLT2 suppression

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.