Discovery of a New Medical Discipline: Nonequilibrium Medicine (NEM) — Proposing a Cross-Cutting Medical Framework Based on Thermodynamic Dynamics, Flux, Dissipation, Adaptation, and Resilience

Nonequilibrium thermodynamics and nonequilibrium physics are established scientific fields with extensive mathematical and theoretical foundations. Their principles have also been applied extensively to biological systems, including metabolism, biochemical reaction networks, molecular processes, cellular organization, energy conversion, fluctuations, dissipation, and dynamic adaptation. In this preprint this work proposes Nonequilibrium Medicine (NEM) as a cross-cutting conceptual and research framework for the systematic organization, integration, and medical application of established nonequilibrium principles. NEM does not propose new laws of thermodynamics, new definitions of entropy, new fundamental nonequilibrium equations, or a replacement for established nonequilibrium physics, nonequilibrium biology, systems biology, network biology, computational biology, bioenergetics, or systems medicine. Instead, NEM proposes a medical synthesis that places established nonequilibrium concepts—including energy and matter flow, thermodynamic driving forces, metabolic flux, chemical and electrochemical gradients, dissipation, entropy production, fluctuations, dynamic stability, perturbation responses, adaptation, and recovery—within a common framework for investigating health and disease. The framework proposes that existing biological and medical measurements can be examined through a nonequilibrium lens. Candidate observables include metabolic, energetic, redox, mitochondrial, inflammatory, physiological, and dynamic variables such as NADH/NAD⁺, NADPH/NADP⁺, ATP/ADP, lactate/pyruvate, oxygen consumption, mitochondrial membrane potential, reactive oxygen species, glutathione redox state, metabolic fluxes, physiological variability, and other measurable system-level variables. These variables are not claimed to be newly discovered NEM biomarkers; rather, NEM proposes that their relationships, temporal dynamics, fluxes, fluctuations, responses to perturbation, and recovery characteristics may provide additional information about biological nonequilibrium states. NEM also proposes that established metabolic and pharmacological interventions may serve as controlled perturbations for experimentally testing nonequilibrium hypotheses. For example, metabolic modulators such as trimetazidine may be investigated as interventions that alter substrate utilization and energy-flow partitioning. The relevant scientific question is not whether these interventions were originally developed under NEM, but whether their effects can be quantitatively understood within a broader nonequilibrium framework and whether such analysis produces experimentally testable and clinically useful information. A central proposition of NEM is that health and disease may be investigated not only through static biomarker concentrations or isolated molecular pathways, but also through the dynamic organization of energy flow, metabolic flux, dissipation, fluctuations, perturbation response, adaptive capacity, and recovery across biological scales. The framework is intended to be applicable across medical disciplines, including cardiology, oncology, neurology, immunology, endocrinology, diabetology, nephrology, pulmonology, hepatology, infectious disease, critical care, aging research, pharmacology, systems medicine, and precision medicine. Importantly, NEM is proposed as a research framework rather than a completed or clinically validated medical theory. Its scientific significance will ultimately depend on empirical investigation. The proposed research program is to identify candidate nonequilibrium variables and relationships, formulate testable hypotheses, conduct controlled perturbation experiments, apply established nonequilibrium mathematical and computational methods, validate findings independently, and determine whether NEM-derived relationships provide reproducible mechanistic, predictive, diagnostic, prognostic, or therapeutic information. The potential scientific contribution of NEM therefore does not depend on creating new fundamental physics. Rather, it lies in determining whether the systematic medical organization and application of established nonequilibrium knowledge can generate experimentally validated relationships or clinically useful information that is not adequately captured by isolated disease-specific measurements or existing disciplinary approaches. In this sense, NEM is proposed as a progressively enrichable cross-cutting framework, in which established nonequilibrium science provides the foundation, existing biological and medical measurements provide candidate observables, experimental interventions provide controlled perturbations, and empirical research determines which nonequilibrium relationships have genuine medical significance.