Cardiac fibrosis and heart failure: Metabolic stress, circadian dysregulation, and extracellular matrix remodeling

Diabetes is a major risk factor for heart failure and drives a distinct cardiomyopathic phenotype characterized by oxidative stress, metabolic inflexibility, mitochondrial dysfunction, and progressive myocardial remodeling. Central to this process is cardiac fibrosis, marked by excessive extracellular matrix deposition, increased myocardial stiffness, and impaired mechanotransduction. Emerging evidence identifies circadian rhythm disruption as an under recognized modifier of diabetic cardiac fibrosis. The circadian clock regulates daily oscillations in myocardial metabolism, redox balance, inflammatory signaling, and extracellular matrix turnover, thereby maintaining cardiac homeostasis. However, modern urbanization has introduced chronic exposure to artificial light at night, particularly blue light from digital devices, which suppresses melatonin and desynchronizes central and peripheral clocks. In diabetes, loss of circadian regulation amplifies TGF-β signaling, Rho-A/ROCK-mediated mechanotransduction, oxidative stress, and myofibroblast transformation. Understanding how circadian misalignment accelerates profibrotic remodeling may reveal novel chronotherapeutic strategies to reduce cardiac fibrosis and heart failure risk.