Integrated liver transcriptomic data reveal differences in aging-associated regulation between metabolic dysfunction-associated steatotic liver disease and normal liver aging

BACKGROUND: Age-related molecular trajectories of metabolic dysfunction-associated steatotic liver disease (MASLD) remain insufficiently characterized, limiting age-stratified risk assessment and intervention. OBJECTIVE: To test whether MASLD-related molecular changes with age merely reflect accelerated physiological aging or represent a disease-specific divergence. METHODS: We utilized public transcriptomic data from normal liver and MASLD samples to identify differential transcriptomic signals. We employed Spearman correlation analysis and generalized additive models (GAM) for nonlinear age-related trajectory modeling, and functional enrichment analysis for signaling pathway characterization. RESULTS: We integrated 1,354 public liver transcriptome samples from GEO and GTEx databases to construct a cross-age cohort. Differential expression and age-correlation analyses showed minimal overlap (only 22 genes) between age-associated genes in MASLD and controls, with some genes displaying opposite age-related trends. GAM identified four major expression patterns in MASLD-stable, early-life change, late-life acceleration, and mid-life fluctuation-with trajectory inflection time points around ages ~35 and ~75. Functional enrichment indicated that control age-associated genes mainly involved classical cell cycle processes, whereas MASLD changes were enriched for protein deubiquitination, proteostasis imbalance, and p53-related stress and apoptotic signaling. Many MASLD age-associated genes were also associated with fibrosis stage or NAS, largely in concordant directions. CONCLUSION: MASLD exhibits disease-specific age-related transcriptional remodeling characterized by dysregulation of proteostasis and deubiquitination pathways, activation of cellular stress-response programs, and enrichment of p53-associated apoptotic signaling, rather than a simple acceleration of physiological aging.