Hepatocellular carcinoma (HCC) is often associated with the overexpression of multiple proteins and genes. For instance, patients with HCC and a high expression of the glypican-3 (GPC3) gene have a poor prognosis, and noninvasive assessment of GPC3 expression before surgery is helpful for clinical decision-making. Therefore, our primary aim in this study was to develop and validate multisequence magnetic resonance imaging (MRI) radiomics nomograms for predicting the expression of GPC3 in individuals diagnosed with HCC.We conducted a retrospective analysis of 143 patients with HCC, including 123 cases from our hospital and 20 cases from The Cancer Genome Atlas (TCGA) or The Cancer Imaging Archive (TCIA) public databases. We used preoperative multisequence MRI images of the patients for the radiomics analysis. We extracted and screened the imaging histologic features using fivefold cross-validation, Pearson correlation coefficient, and the least absolute shrinkage and selection operator (LASSO) analysis method. We used logistic regression (LR) to construct a radiomics model, developed nomograms based on the radiomics scores and clinical parameters, and evaluated the predictive performance of the nomograms using receiver operating characteristic (ROC) curves, calibration curves, and decision curves.Our multivariate analysis results revealed that tumor morphology (P=0.015) and microvascular (P=0.007) infiltration could serve as independent predictors of GPC3 expression in patients with HCC. The nomograms integrating multisequence radiomics radiomics score, tumor morphology, and microvascular invasion had an area under the curve (AUC) value of 0.989. This approach was superior to both the radiomics model (AUC 0.979) and the clinical model (AUC 0.793). The sensitivity, specificity, and accuracy of 0.944, 0.800, and 0.913 for the test set, respectively, and the model's calibration curve demonstrated good consistency (Brier score =0.029). The decision curve analysis (DCA) indicated that the nomogram had a higher net clinical benefit for predicting the expression of GPC3. External validation of the model's prediction yielded an AUC value of 0.826.Our study findings highlight the close association of multisequence MRI imaging and radiomic features with GPC3 expression. Incorporating clinical parameters into nomograms can offer valuable preoperative insights into tailoring personalized treatment plans for patients diagnosed with HCC.2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.