A [68Ga]-labeled PDGFRβ-targeting peptide PET probe for assessing MASH-related fibrosis in diet-induced preclinical models and human liver specimens.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatocellular injury, inflammation, and progressive fibrosis, yet current non-invasive tests do not directly assess the cellular drivers of fibrogenesis. Platelet-derived growth factor receptor beta (PDGFRβ) is highly expressed on activated hepatic stellate cells (aHSC), a major effector cell population in MASH. A PDGFRβ-targeted peptide was synthesized and radiolabeled with gallium-68. We investigated whether PDGFRβ-targeted PET imaging could enable non-invasive molecular assessment of MASH severity. Dynamic PET/CT, ex vivo autoradiography, histopathology, immunostaining, western blotting, and qPCR were performed in graded MASH mouse models induced by choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and methionine-choline-deficient (MCD) diet, with human MASH liver specimens for validation. Both CDAHFD and MCD models developed progressive steatohepatitis and fibrosis accompanied by increasing hepatic PDGFRβ expression. PDGFRβ colocalized with αSMA positive aHSC populations and the proportion of PDGFRβ/αSMA double positive cells increased markedly in diseased livers. PET imaging demonstrated progressively increased hepatic uptake of the 68Ga-labeled PDGFRβ probe with worsening disease severity in both models. Probe uptake quantified by SUV and AUC paralleled histological fibrosis, PDGFRβ protein expression, and fibrosis-related gene transcription. Autoradiography confirmed specific probe binding in mouse liver sections. In human MASH specimens, PDGFRβ expression and probe binding similarly increased with pathological severity and correlated with fibrosis-associated markers. PDGFRβ-targeted PET imaging enables non-invasive molecular visualization of aHSC and provides a quantitative imaging approach for grading MASH severity. These findings support PDGFRβ as a candidate imaging biomarker for biologically active fibrogenesis in MASH and provide a rationale for future clinical translation.