<scp>SHBs</scp> Mitigates Sorafenib‐Induced Apoptosis in Hepatocellular Carcinoma via Activation of <scp>RAF1</scp>/<scp>MEK</scp>/<scp>ERK</scp> Signaling Pathway

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, with a significant association to hepatitis B virus (HBV) infection, which has been shown to drive HCC progression. Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced HCC. However, recent studies indicate that HBV infection may confer resistance to sorafenib treatment. The small hepatitis B surface antigen (SHBs), the most abundant HBV viral protein, has been implicated in HCC development, yet its role in sorafenib resistance is unclear. This study demonstrates that SHBs promotes sorafenib resistance in HCC cells and xenograft models by inhibiting apoptosis. Upon sorafenib treatment, SHBs expression was found to enhance the RAF1/MEK/ERK signaling pathway, as evidenced by increased phosphorylation of ERK and MEK. Inhibition of ERK activity with U0126 countered SHBs effects on sorafenib-induced apoptosis, cleaved caspase-3, and cellular proliferation. Mechanistically, SHBs binds to protein tyrosine phosphatase non-receptor type 1 (PTPN1), enhancing its phosphorylation, which subsequently dephosphorylates the protein tyrosine phosphatase interacting protein 51 (PTPIP51). This dephosphorylation promotes RAF1 recruitment to the 14-3-3β complex, leading to activation of the RAF1/MEK/ERK pathway. These findings suggest that SHBs prevents sorafenib-induced apoptosis in HCC cells by binding to PTPN1 and stimulating the formation of the PTPIP51/14-3-3β/RAF1 complex, thereby activating the RAF1/MEK/ERK signaling pathway. This mechanism provides insight into HBV-induced sorafenib resistance in HCC, highlighting SHBs as a potential target for overcoming treatment resistance in HBV-related HCC.