Creatine as a mitochondrial theranostic in predictive, preventive, and personalized medicine

Abstract Creatine, traditionally recognized for its role in skeletal muscle energy metabolism, is increasingly emerging as a mitochondria-targeted theranostic agent with significant relevance to the framework of predictive, preventive, and personalized medicine (PPPM). However, several critical gaps currently limit its translation into clinical practice: (1) the lack of sensitive and standardized biomarkers for early detection of bioenergetic deficits, (2) limited incorporation of creatine profiling into predictive risk models, (3) insufficient personalization of supplementation strategies despite known interindividual variability in transporter function, endogenous synthesis, and tissue kinetics, and (4) underdeveloped clinical validation of advanced creatine formulations and delivery systems. This mini review addresses these unmet needs by consolidating evidence on creatine’s multifaceted biological functions—including stabilization of mitochondrial membranes, regulation of oxidative stress, support of mitochondrial biogenesis, and modulation of apoptotic signaling—across physiological and pathological states. By sustaining ATP homeostasis via the creatine kinase–phosphocreatine system and influencing mitochondrial dynamics and redox balance, creatine represents both a therapeutic and diagnostic candidate for diseases characterized by impaired bioenergetics. From a PPPM perspective, creatine profiling through biofluids, tissue sampling, and advanced imaging (e.g., proton magnetic resonance spectroscopy) offers a minimally invasive approach for early detection, patient stratification, and monitoring of mitochondrial function. Personalized intervention strategies—guided by molecular and phenotypic profiling—have the potential to maximize efficacy and minimize risk, while creatine loading or depletion tests may serve as functional biomarkers of mitochondrial reserve capacity and supplementation responsiveness. Finally, integration of creatine-centered diagnostics and therapeutics with multi-omics data, computational modeling, and digital health monitoring could overcome existing translational barriers. By reframing creatine from a sports nutrition supplement to a scalable, safe, and cost-effective component of mitochondrial medicine, this review outlines a pathway to address current diagnostic, predictive, and therapeutic deficits, ultimately supporting proactive, systems-level approaches to health maintenance and disease prevention.