CHAF1B: the hidden culprit behind sorafenib resistance in hepatocellular carcinoma

<b>Introduction:</b> Chromatin assembly factor 1B (CHAF1B), a pivotal regulator of chromatin assembly following DNA replication, has been implicated in oncogenic processes. However, its role in sorafenib resistance and potential anti-tumor mechanisms in hepatocellular carcinoma (HCC) remain unclear. This study has sought to elucidate CHAF1B's therapeutic potential and its potential synergistic role with sorafenib in overcoming chemoresistance. <b>Methods:</b> In this study, bioinformatics, immunohistochemistry, western blot, CCK8, colony formation, transwell migration and invasion, and flow cytometry were performed to analyze the correlation between CHAF1B and sorafenib resistance in HCC. Furthermore, RNA sequencing (RNA-seq), combined with signaling pathway-specific inhibitors, was used to elucidate the specific role of CHAF1B in sorafenib resistance of HCC and its related mechanism. <b>Results:</b> CHAF1B was significantly upregulated in HCC tissues and sorafenib-resistant HCC cells, with elevated expression correlated with reduced survival probability in HCC patients. Moreover, high CHAF1B levels predicted poorer clinical outcomes in sorafenib-treated patients. Functional assays revealed that CHAF1B promotes HCC cell proliferation, migration, and invasion, while also enhancing resistance to sorafenib. In contrast, knockdown of CHAF1B significantly increased sorafenib-induced inhibition of proliferation and cell death. Mechanistically, CHAF1B facilitated malignant phenotypes via activation of the PI3K/Akt/HIF-1α pathway. Furthermore, blockade of PI3K/Akt/HIF-1α signaling partially attenuated the CHAF1B-mediated sorafenib resistance. <b>Conclusion:</b> CHAF1B is a key regulator of sorafenib resistance, and targeting CHAF1B in conjunction with sorafenib may represent a promising therapeutic approach for HCC by modulating the PI3K/Akt/HIF-1α signaling axis.