Beyond biochemical recovery: Persistent molecular and cellular states after acute hepatotoxic injury

BACKGROUND: Recovery from acute hepatotoxic injury (AHTI), including drug-induced liver injury, is conventionally defined by normalization of serum biomarkers and resolution of clinical and histopathological abnormalities. However, biochemical normalization may not reflect structural and functional restitution of the hepatic microenvironment. METHODS: This hypothesis-driven narrative review brings together findings from experimental and translational evidence on molecular and cellular alterations persisting after AHTI. It distinguishes established findings from proposed mechanisms and long-term consequences, emphasizing limitations in evidence regarding clinical significance. RESULTS: Emerging studies demonstrate that molecular, cellular, and spatial alterations may persist after serum biomarkers normalize. Regeneration driven by oxidative stress, replicative demand, metabolic rewiring, and developmental pathway reactivation restores tissue mass but may reshape clonal dynamics and leave spatially restricted molecular imprints. These alterations involve hepatocytes and non-parenchymal cells, including hepatic stellate cells, macrophages, and endothelial cells. Whether persistent signatures reflect adaptive remodeling, delayed resolution, or stable scarring remains unclear. Although clinical evidence has not established whether resolved AHTI alters susceptibility to a subsequent "second hit," incomplete molecular resolution challenges definitions of hepatic resilience. Current findings derive predominately from intrinsic toxicity models and should not be extrapolated across etiologies without direct comparison. CONCLUSION: Persistent molecular scars suggest that biochemical normalization does not indicate complete hepatic recovery. Integrating spatial and single-cell modalities into toxicology frameworks may improve post-injury monitoring, identify biomarkers of resolution, and inform regulatory safety standards. Because human liver tissue is rarely accessible for these analyses, clinical translation will likely require minimally invasive approaches, including circulating biomarkers and extracellular vesicles.