The unmasking of two-faced portrait in sorafenib-resistant surroundings via systems pharmacology concept: a brightness or a silhouette

This study aimed to identify novel key targets and mechanisms for repurposing strategies and mitigating sorafenib (SFB) resistance using the GEO transcriptomic dataset GSE94550 within a systems pharmacology framework. Potential counteracting molecules against SFB were retrieved from chemical repositories, followed by molecular docking tests (MDT), Kaplan–Meier survival analysis, and density functional theory (DFT) assessments to evaluate therapeutic potential. PPI networks were constructed using STRING and R to characterize the relationships between upregulated and downregulated genes. The most relevant signalling pathways associated with major targets were determined to elucidate the upstream regulatory mechanisms. Among the differentially expressed genes, APOB emerged as a pivotal regulator (log2FC ≥ +2 or ≤ −2), modulating fifteen genes, including eleven upregulated and four downregulated nodes. At stricter thresholds (log2FC ≥ +3 or ≤ −3 and ≥ +4 or ≤ −4), CD44 was identified as a key upregulated target. Its inhibition – particularly by verbacoside – was strongly associated with suppression of the ECM–receptor interaction pathway, suggesting a significant therapeutic axis. This study illuminates the molecular landscape of SFB-resistant environments through an integrative network approach and highlights verbacoside as a promising agent capable of attenuating SFB resistance, supporting its potential role in combination therapy.