SGLT2 inhibitors (SGLT2i, or gliflozins) were developed to treat diabetes but have since demonstrated cardiovascular and renal benefits that extend well beyond glycemic control, with emerging evidence for protective effects in neurodegeneration, cancer, and other metabolic diseases. Despite this expanding therapeutic scope, SGLT2i continue to be studied and prescribed largely as a single drug class, even though clinical data suggest meaningful differences in efficacy and adverse effects among individual agents. This review synthesizes findings from in vitro, ex vivo, and in vivo studies that directly compare SGLT2i to identify drug-specific, SGLT2-independent mechanisms, particularly on NHE activity and energetic metabolism. These studies indicate that noncanonical SGLT2i effects arise from a mix of shared and drug-specific mechanisms rather than uniform class effects, underscoring the need for further direct comparisons to guide precision use of these drugs across an increasingly broad range of indications.
Atherosclerosis is a chronic inflammatory disease driven by coordinated dysfunction of endothelial cells, macrophages, and vascular smooth muscle cells (vSMCs). Increasing evidence identifies E3 ubiquitin ligases as central regulators of vascular homeostasis by controlling protein stability, signaling, and cellular plasticity through the ubiquitin–proteasome system. Rather than functioning as isolated regulators of individual substrates, E3 ligases integrate inflammatory, metabolic, oxidative, and mechanical cues to orchestrate the cell-state transitions that underlie plaque initiation, progression, and stability.In this Review, we highlight recent advances in the roles of E3 ubiquitin ligases across the major vascular cell types involved in atherosclerosis. In endothelial cells, E3 ligases regulate barrier integrity, inflammatory activation, endothelial-to-mesenchymal transition, and vascular cell crosstalk. In macrophages, they coordinate cholesterol homeostasis, inflammatory signaling, and efferocytosis, thereby influencing foam cell formation and plaque remodeling. In vSMCs, E3 ligases govern phenotypic plasticity, osteogenic differentiation, and extracellular matrix homeostasis, ultimately determining fibrous cap integrity and vascular calcification. These shared mechanisms identify ubiquitination as a systems-level regulator of vascular biology rather than a collection of cell-type-specific pathways.We further discuss how these mechanistic insights are driving the development of targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders, as emerging therapeutic approaches for cardiovascular disease. Defining vascular ubiquitination networks and expanding the repertoire of druggable E3 ligases will be critical for translating ubiquitin biology into precision therapies that restore vascular homeostasis and improve outcomes in atherosclerotic cardiovascular disease.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors protect kidney function in diabetic and non-diabetic chronic kidney disease. By reducing proximal sodium-glucose transport, they initiate nephron-wide adaptations in transport workload, solute delivery, oxygen demand, tubuloglomerular feedback, glomerular vascular tone, and metabolic and inflammatory signaling. These responses may reduce mitochondrial stress, ferroptosis, inflammation, maladaptive repair, and fibrosis, while natriuresis, altered substrate use, and cardiac unloading provide additional protection. Although large outcome trials establish clinical efficacy, the contributions of individual pathways remain uncertain and may vary with diabetes type, nephron number, disease stage, and background therapy. This review integrates experimental and clinical evidence into a multiscale physiological model, distinguishes established effects from mechanistic hypotheses, and identifies priorities for physiological phenotyping, spatial and single-cell profiling, biomarker-guided combination therapy, and causal systems-level studies.
