• Identification of ALB as a central hub gene in sorafenib-resistant HCC and its high-affinity binding with β-sitosterol from Cordyceps sinensis • Revealing a unique resistance-reversal mechanism via the ALB/T4/T3/AKT pathway, distinct from sorafenib's action • Establishing a novel network pharmacology framework bridging TCM and modern oncology for HCC therapy Introduction: Hepatocellular carcinoma (HCC) constitutes approximately 80% of primary liver malignancies, with sorafenib as its first-line therapy often exhibiting limited efficacy due to drug resistance. Aim: This study systematically explored the mechanisms underlying sorafenib resistance and screened potential Traditional Chinese Medicine (TCM) - derived bioactive compounds as candidates for future investigation through integrated bioinformatics and network pharmacology approaches. Materials and methods : Sorafenib resistance – related differentially expressed genes (DEGs) (|log2FC| ≥1, adj. P <0.01) were extracted from HCC GEO datasets using GEO2R. Protein-protein interaction (PPI) networks were constructed via STRING and analyzed using Cytoscape. Functional enrichment analysis, including GO and KEGG pathway assessment, was performed using DAVID. Key hub genes were screened (cytoHubba), and potential TCM bioactive compounds were predicted (Coremine). Molecular docking simulations (AutoDock) and 3D structural visualization (PyMOL) were performed to validate binding affinities between candidate compounds and hub gene-encoded proteins. Molecular dynamics (MD) simulations were conducted to assess the stability and elucidate the binding mechanisms. Results : We identified 645 significant DEGs in sorafenib-resistant HCC. PPI network analysis revealed eight hub genes, with ALB displaying the highest connectivity, identifying it as a topologically central gene within the resistance-associated molecular network. Molecular docking analysis predicted a high-affinity interaction between β-sitosterol (a bioactive compound of Cordyceps sinensis ) and ALB. MD simulations indicated stable binding of β-sitosterol and cordycepin to ALB, with binding modes distinct from that of sorafenib. These computational findings generate the hypothesis that such compounds might modulate ALB-associated pathways, warranting experimental validation to explore their potential relevance in combination therapy. Conclusion : Our integrative computational analysis identified a multi-gene network associated with sorafenib-resistant in HCC, with ALB emerging as a topologically central hub. Computational modeling predicts that β-Sitosterol binds to ALB with high affinity in a mode distinct from sorafenib. These hypothesis-generating findings require validation through subsequent in vitro and in vivo experiments.
Jia et al. (Sun,) studied this question.