MASLD-Mitochondrial Digital Twin: Mapping mitonuclear epistasis to predict disease trajectory and systemic bioenergetic homeostasis

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic disorder with marked clinical heterogeneity and divergent outcomes. Current pathophysiological models fail to fully account for inter-individual variation in progression toward steatohepatitis and systemic multimorbidity. This Perspective posits the mitochondrion as an integrative functional hub where genomic predisposition, epigenomic plasticity, and bioenergetic signaling converge to shape the disease's longitudinal trajectory. We synthesize evidence from the mitonuclear interactome—the co-evolutionary and functional coordination between nuclear and mitochondrial genomes, hepatic epigenomic remodeling, and circulating mitochondrial metabotypes to propose a unified systems biology framework: the MASLD-Mitochondrial Digital Twin (MASLD-MDT). This multiscale platform integrates high-resolution biological data—including single-cell mitochondrial DNA (mtDNA) heteroplasmy, NAD+ redox dynamics, and the systemic efflux of mitochondrial-derived peptides (MDPs)—to simulate individualized disease kinetics. By reframing MASLD as a systemic mitochondriopathy, the MASLD-MDT could quantify critical bioenergetic thresholds, providing a novel metric for risk stratification and the in silico optimization of therapeutic deployment. This hypothesis-oriented instrument aims to advance the field toward a mitochondrial precision medicine strategy, enabling the discovery of targeted interventions to intercept multi-organ compromise.