Trained Immunity and Persistent Myeloid Responsiveness in MASH

Metabolic dysfunction-associated steatohepatitis (MASH) involves hepatocellular injury, myeloid activation, and fibrotic remodeling that may resolve unevenly following metabolic improvement. Whether previous injury leaves a functionally consequential innate immune imprint remains unresolved. This review evaluates trained immunity as a candidate mechanism linking exposure history to persistent hepatic myeloid responsiveness. We distinguish continued activation by lipotoxic and stromal signals from responses retained after stimulus withdrawal, macrophage replacement, and hematopoietic progenitor programming. Evidence from Kupffer cells, monocyte-derived macrophages, and lipid- or scar-associated populations reveals divergent inflammatory, efferocytosis, and matrix remodeling functions. Receptor-dependent lipid handling intersects with glycolysis, citrate-derived acetyl-CoA, serine and one-carbon metabolism, NAD+ availability and histone methylation, acetylation, and lactylation. These pathways explain how metabolic inputs regulate inflammatory competence, but their alteration during active MASH does not establish immune memory. Rested monocyte training models provide stronger temporal evidence than most disease-specific studies, whereas protective TREM2-dependent responses caution against indiscriminate suppression of disease-associated macrophages. Establishing a contribution to MASH recurrence requires lineage-resolved investigations spanning injury, regression, and rechallenge, with interventions separating memory establishment, maintenance, and effector output. If exposure-dependent myeloid memory contributes causally to MASH recurrence, targeting maladaptive responsiveness could complement injury control while preserving hepatic repair.