STAT3 inhibitors combined with retinol binding protein 4 complex ameliorate DEN-induced liver carcinogenesis in mice and induce apoptosis via GRP78/ATF6/CHOP signaling pathway.

Primary liver cancers are most commonly hepatocellular carcinomas (HCCs), often developing in the context of chronic liver diseases. It is characterized by aggressive growth and a poor prognosis despite treatment efforts. Hence, this present study was conducted using STAT3 inhibitors (S3I) combined with Retinol-binding protein 4 (RBP4), a combination that was confirmed by molecular docking analysis with binding score - 7.0 kcal/mol. Additionally, S3I@RBP4 exhibited protective effects against diethylnitrosamine (DEN) induced liver carcinoma in mouse models. The anti-tumor potential against human HCC in HepG2 and Hep3B cells was examined using MTT assay, which demonstrated that the treatment works by inducing apoptosis and inhibiting cell proliferation. In vitro, S3I@RBP4 treatment effectively suppressed HepG2 and Hep3B cell proliferation and increased intracellular ROS accumulation. Remarkably, in vitro, S3I@RBP4 induced caspase-dependent apoptosis in HCC cells by activating the GRP78/ATF6/CHOP signaling pathway. Conversely, in vivo, it counteracted DEN-induced effects by mitigating hepatic oxidative stress, reducing oxidative DNA damage and decreasing tumor-specific markers. In vivo studies further confirmed that S3I@RBP4 treatment mitigated liver damage, inflammation, and proliferation in mice exposed to DEN. The study highlights the potential of S3I@RBP4 for DEN-induced liver cancer therapy in mice. Over time, treated mice showed that inhibited cancer proliferation in histological analyses, which suggests that S3I@RBP4 is a promising candidate with chemotherapeutic potential against HCC. This work presents S3I@RBP4 as a safe and effective therapeutic option for liver cancer.