Regenerative failure in metabolic dysfunction-associated steatohepatitis: The entrapped progenitor model and precision repair

Background Metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as a leading cause of cirrhosis and hepatocellular carcinoma. Despite recent Food and Drug Administration approval of metabolic modulators, limited efficacy in advanced fibrosis highlights an urgent need for therapies targeting downstream cellular mechanisms. Scope of review This review examines the paradoxical hepatic progenitor cell (HPC) response in MASH. While HPC activation manifests histologically as the ductular reaction, theoretically a regenerative process, it becomes dysfunctional within the chronically inflamed fibrotic microenvironment, paradoxically promoting fibrosis and tumorigenesis rather than effective regeneration. We synthesize evidence on the multicellular HPC niche and the coordinated roles of key developmental pathways Wnt/β-catenin, Notch, transforming growth factor-beta (TGF-β), Hedgehog, and YAP/TAZ in governing this maladaptive fate. The novelty of this review lies in three contributions: (1) the proposition of the “Entrapped Progenitor Model” wherein pathological niche-imposed recontextualization of pro-regenerative signals, not intrinsic HPC dysfunction, is the primary determinant of regenerative failure; (2) a mechanistic synthesis of five interdependent developmental pathways (Wnt/β-catenin, Notch, TGF-β, Hedgehog, YAP/TAZ) converging to predetermine HPC fate; and (3) the advancement of a “precision regenerative hepatology” framework integrating spatial omics-guided niche mapping, cell-type-targeted delivery platforms, and patient-derived bioengineered models as a clinically translatable therapeutic roadmap. Key message In MASH, the pathological niche predetermines HPC fate through reprogramming of pro-regenerative signals into dominant pro-fibrotic and pro-biliary cues. Previous therapeutic strategies have failed due to intrinsic biological constraints: tumorigenicity and poor engraftment of cell therapies, and unacceptable systemic toxicity from pathway pleiotropy. Conclusion Restoration of liver regeneration in MASH requires a paradigm shift from nonspecific pathway modulation to precision, spatiotemporal control of the disease microenvironment. We present a “precision regenerative hepatology” framework integrating spatial omics-guided niche mapping, targeted delivery platforms, and advanced patient-specific preclinical models.