Injectable multi-component hydrogel as an inhibitor of choline kinase α achieved the treatment of malignant ascites by inhibiting PI3K/AKT/mTOR signaling pathway

INTRODUCTION: Primary liver cancer remains the third leading cause of global cancer-related mortality, with hepatocellular carcinoma (HCC) constituting the predominant histological subtype. The development of malignant ascites in advanced HCC patients signifies metastatic progression and portends poor clinical outcomes, presenting a formidable therapeutic challenge. OBJECTIVES: This study aimed to engineer a natural small-molecule hydrogel for anti-tumor treatment, in order to reduce the production of ascites and achieve the dual therapeutic effect. METHODS: H NMR and molecular dynamics. Small animal imaging techniques were utilized to evaluate the retention of EP-GA in vivo. The H22 ascites tumor model was established, and antitumor mechanism was verified by transcriptomics, metabolomics and flow cytometry. RESULTS: The EP-GA hydrogel formed uniform nanoparticles with an average diameter of approximately 200 nm. Rheological characterization confirmed its excellent injectability. Using marker components euphol (EPH) and glycyrrhizic acid (GA) to analyze the self-assembly process, hydrogen bond interactions occurred between euphol's hydroxyl group and GA's hydrophilic domain. In H22 subcutaneous HCC xenograft models, EP-GA demonstrated significant tumor growth suppression, with a tumor growth inhibition rate (IRG) of 68.63 % at the dosage of 18.75 mg/kg. Combined transcriptomic and metabolomic analysis reveals that it inhibits tumor progression by suppressing choline kinase alpha, regulating the PI3K/AKT/mTOR pathway, and inducing ROS generation and mitochondrial membrane potential decline. CONCLUSION: This excipient-free nanohydrogel platform effectively circumvents carrier-related toxicity while demonstrating powerful therapeutic efficacy against HCC, and this platform is a promising new strategy for HCC prevention and treatment.