Dieckol from brown algae targeting the Hepatocellular Carcinoma pathway: A computational pharmacology study

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, underscoring the urgent need for novel, multi-target therapeutics. This study systematically evaluates Dieckol, a phlorotannin from brown algae, using a dry-lab pipeline integrating quantum chemical calculations, transcriptomic data mining, network pharmacology, molecular docking, molecular dynamics (MD), and ADMET-toxicity prediction. Density Functional Theory (DFT) analysis revealed favorable electronic properties for selective bio-interactions, including a narrow HOMO–LUMO gap (0.119 eV) and high electron-accepting capacity. From 313 predicted targets and 7325 HCC-associated genes, 33 overlapping genes were identified, enriched in cell cycle, apoptosis, and oncogenic signaling pathways, particularly hsa05225 (HCC pathway). Protein–protein interaction and drug–target–pathway networks highlighted CDKN1A, TP53, DNMT1, AURKA, and MAPK1 as central targets. Molecular docking demonstrated strong binding affinities with key HCC-related proteins (CDKN1A: −10.3 kcal/mol; TP53: −9.5 kcal/mol), supported by stable MD simulations and favorable MMGBSA binding energies (e.g., DNMT1: −362.9 kcal/mol). Dieckol also modulated immune-infiltration signatures of key genes (e.g., PIK3R1, NRAS, CDKN2A), suggesting immunomodulatory potential. Gene and protein expression analyses validated differential upregulation of hub targets in tumor vs. normal liver tissues. In silico ADME profiling revealed low oral bioavailability, poor GI absorption, and selective CYP2C9 inhibition, while toxicity predictions showed no carcinogenicity or genotoxicity but flagged moderate renal and dermal risks. Collectively, our findings position Dieckol as a promising multi-target agent for HCC intervention, warranting further in vitro and in vivo validation.