Thymoquinone-conjugated liposomes improve cytotoxic and proapoptotic effects against hepatocellular cancer by altering the EGFR/ERK/MEK signaling axis.

Modulating the signaling axis between tumors and their environment is one of the key strategies to slow down the progression of hepatocellular carcinoma (HCC). In this study, we aimed to design a polyethylene glycolated liposome loaded with thymoquinone (PEG-TQ-LP) as a delivery system to investigate its effect on HCC progression and the underlying mechanisms in vitro and in vivo. The study revealed the inhibitory effects of PEG-TQ-LP on the proliferation of HCC cells and facilitated apoptosis. The observed effect can be explained by the increased expression of BAX and the decreased expression of BCL2. The activation of p38-MAPK has been implicated in the anti-oncogenic impact of PEG-TQ-LP. This activation was correlated with the dephosphorylation of MEK and ERK. The in vivo study confirmed that PEG-TQ-LP reduces the detrimental effects of free TQ on liver tissue, suppresses tumor growth, and reestablishes the oxidative state equilibrium. Molecular docking analysis demonstrated that TQ docked well with three key targets. The findings from current investigations may represent a novel strategy for the treatment of liver cancer, as PEG-TQ-LP potently promotes apoptosis. This is achieved via thymoquinone's ability to bind to cancer protein targets' active sites, which indicates that it functions similarly to anticancer medications.