Identification of CCNA2 as a Therapeutic Target in Cholangiocarcinoma and Evaluation of Indonesian Jamu-Derived Phytochemicals through Network Pharmacology and Molecular Docking

Abstract

Cholangiocarcinoma (CCA) remains a highly aggressive malignancy with limited therapeutic options and poor prognosis, particularly in Southeast Asia, including Indonesia. The identification of novel molecular targets is essential to improve treatment strategies. This study aimed to identify key therapeutic targets in CCA and evaluate the potential of Indonesian jamu-derived phytochemicals as candidate inhibitors using an integrated computational approach. Differentially expressed genes (DEGs) associated with CCA were analyzed and intersected with disease-related datasets to construct a protein–protein interaction (PPI) network, from which hub genes were identified. Among these, CCNA2, a critical regulator of cell cycle progression, was selected as the primary target due to its central role in tumor proliferation and strong network connectivity. Subsequently, selected phytochemicals derived from Indonesian medicinal plants commonly used in jamu, including Curcuma longa, Curcuma xanthorrhiza, Zingiber officinale, and Kaempferia galanga, were screened for ethnobotanical relevance, their reported anticancer activities in modulating cell cycle progression, and drug-likeness using Lipinski’s rule of five. Molecular docking analysis was performed to evaluate the binding affinity of these compounds against CCNA2. Several phytochemicals demonstrated favorable binding energies comparable to or exceeding that of the native ligand (−8.8 kcal/mol), indicating strong interaction potential within the active site of the protein. The binding interactions were stabilized through hydrogen bonding, hydrophobic interactions, and π- related interactions, suggesting a plausible mechanism for inhibitory activity. This study highlights CCNA2 as a promising therapeutic target in CCA and demonstrates the potential of Indonesian jamu phytochemicals as candidate inhibitors. These findings provide a scientific basis for further experimental validation and support the integration of traditional herbal medicine into modern drug discovery pipelines for cholangiocarcinoma treatment.