Marwa Matboli ^1* Hiba S. Al-Amodi ² ABDELRAHMAN KHALED ³ Radwa Khaled ^4,5 Marwa Ali ¹ Hala F. Kamel ² Manal S. Hamid ¹ Hind A. ELsawi ¹ Eman K. Habib ¹ Ibrahim Youssef ⁶

• ¹ Faculty of Medicine, Ain Shams University, Cairo, Egypt
• ² Umm al-Qura University, Mecca, Saudi Arabia
• ³ Nile University, Giza, Giza, Egypt
• ⁴ Modern University for Technology & Information (MTI), Cairo, Beni Suef, Egypt
• ⁵ Modern University for Information and Technology, Cairo, Cairo, Egypt
• ⁶ Cairo University, Giza, Giza, Egypt

Liver cancer, particularly Hepatocellular carcinoma (HCC), remains a significant global health concern due to its high prevalence and heterogeneous nature. Despite the existence of approved drugs for HCC treatment, the scarcity of predictive biomarkers limits their effective utilization. Integrating diverse data types to revolutionize drug response prediction, ultimately enabling personalized HCC management. In this study, we developed multiple supervised machine learning models to predict treatment response. These models utilized classifiers such as logistic regression (LR), k-nearest neighbors (kNN), neural networks (NN), support vector machines (SVM), and random forests (RF) using a comprehensive set of molecular, biochemical, and immunohistochemical features as targets of three drugs: Pantoprazole, Cyanidin 3-glycoside (Cyan), and Hesperidin. A set of performance metrics for the complete and reduced models were reported including accuracy, precision, recall (sensitivity), specificity, and the Matthews Correlation Coefficient (MCC). Notably, (NN) achieved the best prediction accuracy where the combined model using molecular and biochemical features exhibited exceptional predictive power, achieving solid accuracy of 0.9693 ∓ 0.0105 and average area under the ROC curve (AUC) of 0.94 ∓ 0.06 coming from three cross-validation iterations. Also, found seven molecular features, seven biochemical features, and one immunohistochemistry feature as promising biomarkers of treatment response. This comprehensive method has the potential to significantly advance personalized HCC therapy by allowing for more precise drug response estimation and assisting in the identification of effective treatment strategies.