Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with progressive multi-organ complications affecting the pancreas, heart, white adipose tissue, and bone. Disease development and severity differ markedly between sexes and across stages of progression. A central pathological feature of T2DM is chronic hyperglycemia-induced oxidative stress, largely mediated by reactive oxygen species (ROS). Among ROS-producing enzymes, NADPH oxidase 4 (NOX4) is of particular interest due to its constitutive activity and close coupling to cellular metabolic fluxes.
The overall aim of this project is to define the optimal temporal and tissue-specific window for targeted NOX4 inhibition during obesity-induced T2DM progression and to elucidate its organ- and sex-dependent effects. Using a combination of pharmacological NOX4 inhibition (setanaxib) and genetic NOX4 knockout models, the project systematically investigates early versus late intervention strategies across key metabolic organs. In parallel, it addresses a novel regulatory layer by exploring the interplay between NOX4 signaling and epitranscriptomic RNA modifications (m⁶A/m⁶Am), which are emerging as critical modulators of gene expression, metabolic adaptation, and disease susceptibility.
By integrating redox biology with epitranscriptomic regulation, this project aims to map dynamic, tissue- and sex-specific molecular changes during T2DM development, identify NOX4-dependent regulatory networks, and uncover potential circulating biomarkers of disease progression. The expected outcomes will advance mechanistic understanding of diabetic complications and support the development of precision, stage-specific therapeutic strategies targeting oxidative stress in T2DM.
Supported by the Czech Science Foundation (project no. 26-20409S, 2026–2028; PI: Markéta Hlaváčková, Ph.D.), in collaboration with the Laboratory of Pancreatic Islet Research and the Laboratory of Molecular Physiology of Bone, Institute of Physiology CAS.
