Metabolomics-guided Mechanisms of Mesenchymal Stromal Cell and Exosome Therapies in Chronic Diseases.

Mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) are promising therapies across cardiovascular, inflammatory, metabolic, and neurodegenerative diseases. Metabolomics has revealed how MSCs/EVs reshape host metabolism, but current studies remain fragmented, small, and largely descriptive. Synthesizing evidence across disease models, we identify conserved metabolic checkpoints, succinate and α-ketoglutarate in the TCA cycle, acylcarnitines in fatty acid β-oxidation, and glutathione in redox balance, as recurrent targets linked to therapeutic benefit. Distinct signatures, including polyamine metabolism, bile acid–FXR/TGR5 signaling, and neurotransmitter regulation, provide disease-specific insights. Yet, most studies lack validation and reproducibility, limiting clinical translation. Progress requires larger datasets, targeted assays, integration into randomized trials, and GMP-aligned pipelines. We propose a Metabolomics-Derived MSC Potency Index, a standardized metabolite panel benchmarked against functional assays, as a framework for therapeutic readiness. This approach positions metabolomics not as a descriptive tool but as a translational benchmark guiding MSC/EV therapy development.