Molecular PET imaging of integrin αvβ6 reveals biliary and fibrotic changes in preclinical MASH.

The progression of metabolic dysfunction-associated steatohepatitis (MASH) involves complex crosstalk among hepatocellular injury, inflammation, and ductular reaction-a process characterized by biliary epithelial proliferation and fibrotic activation. Integrin αvβ6, an epithelial-specific receptor largely absent in normal liver but induced under chronic injury, plays a pivotal role in activating latent TGF-β and driving fibrogenesis. Here, we investigated αvβ6 as a molecular imaging biomarker in MASH using a PET-based strategy to non-invasively visualize epithelial fibrotic signaling in vivo. PET/CT imaging and autoradiography studies were performed in MASH mice at different disease stages using [68Ga] DOTA-R01-MG, a radiotracer targeting integrin αvβ6. Tracer uptake was correlated with histopathological changes, immunofluorescent localization of αvβ6, and transcriptional markers of fibrosis, inflammation, and biliary expansion. Human liver biopsy specimens from MASH patients were analyzed as preliminary ex vivo evidence to explore the translational relevance of αvβ6 expression and tracer binding in human fibrotic liver tissue. In both CDAHFD and MCDD models, hepatic [68Ga] DOTA-R01-MG uptake increased progressively with MASH-associated fibrosis. αvβ6 signals were mainly localized to periportal and ductular regions, where they co-localized with expanding CK19+ biliary epithelial cells. Increased tracer uptake and αvβ6 expression were associated with collagen deposition and transcriptional activation of fibrogenic markers, including TGF-β1, α-SMA/Acta2, Col1a1, Vim, and Timp1. In human MASH liver tissue sections, αvβ6 expression and autoradiographic signals also increased with fibrosis stage, supporting the translational relevance of αvβ6-targeted imaging for fibrotic remodeling. This study identifies integrin αvβ6-targeted PET as a potential molecular imaging strategy to map epithelial remodeling in MASH. Ex vivo analyses of human MASH specimens support the translational relevance of this target, although prospective clinical PET studies and longitudinal outcome validation are required before clinical diagnostic application.