Spatial profiling of carbonyl metabolites in diabetic cardiomyopathy by derivatization-assisted ambient mass spectrometry imaging.

Diabetic cardiomyopathy (DCM), a cardiac complication of diabetes, is characterized by diastolic dysfunction, myocardial fibrosis, and structural remodeling. Carbonyl-containing metabolites (CCMs) play a critical role in driving DCM pathogenesis through metabolic dysfunction, oxidative stress, and lipid peroxidation. In this study, we employed an on-tissue chemical derivatization (OTCD)-based air-flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) approach to investigate spatial metabolic alterations of CCMs in the diabetic rat heart. This method enabled the spatial profiling of 369 CCMs-including 137 fatty aldehydes (FALs), 214 oxo fatty acids (OFAs), and 18 sterol-type lipids (STs)-across cardiac tissue sections. This expanded metabolite coverage revealed marked spatial heterogeneity in cardiac metabolism. Comparative analysis between diabetic and control rats identified 162 significantly altered CCMs, highlighting localized metabolic dysregulation associated with DCM. To explore potential therapeutic interventions, we further evaluated the metabolic impact of ferulic acid, a candidate agent for myocardial protection. High-dose ferulic acid treatment significantly modulated 43 differential CCMs, attenuated pyruvate accumulation, restored fatty aldehyde levels, and improved the profile of oxidized fatty acids. These findings suggest that ferulic acid ameliorates metabolic dysfunction by exerting antioxidant and anti-inflammatory effects, while enhancing mitochondrial function and lipid metabolism. Overall, this study demonstrates the utility of OTCD-AFADESI-MSI for spatially resolved metabolomic analysis of carbonyl stress in DCM and supports the therapeutic potential of ferulic acid in managing diabetic heart injury.