Elucidating <i>DENND5A</i> as a Therapeutic Target for Hepatocellular Carcinoma with Integrative Insights from Spatial Transcriptomics and Molecular Docking Approaches

Hepatocellular Carcinoma (LIHC) represents the most prevalent variant of liver malignancy and constitutes a primary contributor to cancer-associated mortality, frequently identified at advanced stages of the disease. This investigation examines the significance of the DENND5A oncogene in LIHC through a thorough examination of its expression levels, methylation status, somatic mutations and interactions with the immune microenvironment. By employing diverse bioinformatics platforms — including GEPIA2, OncoDB, cBioPortal, PreCog and TIMER 2.0 — we discerned a pronounced overexpression of DENND5A, thereby establishing it as a salient biomarker for LIHC. Methylation assessments revealed hypomethylation in LIHC specimens, whereas somatic mutations were found to correlate with elevated mRNA levels, underscoring DENND5A as a promising therapeutic candidate. Moreover, this research investigates the therapeutic ability of a bioactive–antibiotic conjugate comprising Eridictyol and carbapenem via molecular docking by using PyRx. The molecular docking results show that Eriodictyol has a binding energy of −7.4 kcal/mol, while carbapenem has a binding affinity of −4.1 kcal/mol. The E-C conjugate was determined to have a binding affinity of −9.5 kcal/mol. The Swiss ADMET evaluation revealed advantageous pharmacokinetic characteristics, including commendable human intestinal absorption, albeit with restricted permeability across the blood–brain barrier. Molecular dynamics simulations validated the structural integrity and dynamic behavior of the Eriodictyol–Carbapenem conjugate in conjunction with DENND5A, thereby indicating its promise as an innovative therapeutic approach for hepatocellular carcinoma. Our results position DENND5A as a noteworthy biomarker and therapeutic target for LIHC, with the Eriodictyol–Carbapenem conjugate presenting a novel pathway for treatment.