The clock of the MASH -A quantum-inspired approach of the thermal time theory applied to mitochondrial dysfunction in...

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) remains a major liver disorder worldwide, with mitochondrial dysfunction supposed as a central driver of its progression. While classical models focus on metabolic imbalances, emerging evidence suggests quantum biology processes-electron tunneling, proton transfer, and spin-dependent chemistry-may critically influence mitochondrial efficiency and oxidative stress. Here, we used a non-commutative algebraic framework-like modeling the MASLD progression as a breakdown of quantum-like coherence, where lipid accumulation and ROS disrupt a mitochondrial-like "thermal time," driving the pathological transitions. Using finite-dimensional von Neumann algebras, we represented key observables (ATP, ROS, GSH, ΔΨm, Electron flux) as matrices with diagonal (concentration, membrane potential) and off-diagonal (flux) components, capturing the dynamics of biological transitions in mitochondria fitted for healthy, obese, obese_MASL, obese_MASH and obese_fibrosis-like states. Simulations revealed resilience mechanisms in the early disease states in normal biological configuration. Under stress, the model predicts modified biological dynamics with transitions for where a specific disease state became an irreversible trap state due to deformed energy landscapes. This behaviour also contributed to show potential disease reversibility. Numerically, the model proposed dynamics of biomarkers such as entropies and transition rates associated with disease state probabilities. Due to the quantum-like framework, the local dynamics emerged with their own time cycles, that we called the "clock of the MASH", driving the disease state transitions. The model is still conceptual and not yet predictive, however, by reframing MASLD as a quantum-thermodynamic-inspired disorder, this work bridges theory with translational potentials, offering new avenues for drug discovery in metabolic liver diseases by pinpointing underlying quantum-like mechanisms as a potential therapeutic target.