Background <p>Hepatitis B virus (HBV) infection is the most important cause of hepatocellular carcinoma (HCC), which is mainly caused through chronic liver inflammation and sustained viral activity. Although C-reactive protein (CRP) is known to regulate inflammatory responses, its exact role in HBV replication as well as related tumor progression is still to be elucidated.</p> Methods <p>CRP expression was modulated in HepG2.2.15 cells and murine models by lentiviral as well as plasmid vector systems. The effects on HBV replication, cancer cell proliferation, apoptosis, as well as tumor growth were assessed through qRT-PCR, Western blotting, ELISA, as well as immunohistochemistry. To find the CRP-related signaling pathways, like IL-6-STAT3 as well as NF-κB, transcriptome sequencing, including gene set enrichment analysis (GSEA) was utilized.</p> Results <p>CRP overexpression was found to elevate HBV replication through the increase of cccDNA, pgRNA, as well as viral protein synthesis, and the promotion of cell proliferation and migration and reducing apoptosis. On the contrary, silencing CRP leads to a remarkable decrease in HBV replication as well as viral protein levels, while tumor growth slows down in cellular and animal models. Transcriptomic analyses showed that CRP activates some key inflammatory pathways, including IL-6-STAT3 as well as NF-κB, and has an influence on other oncogenic processes, such as oxidative stress as well as JAK-STAT signaling. CRP knockdown reduced inflammatory cytokine expression, such as TNF-α as well as IL-6, and at the same time upregulated anti apoptotic factors, including BCL-2.</p> Conclusion <p>CRP plays a central role in HBV-driven HCC progression by modulating inflammatory signaling pathways and promoting a tumor-supportive environment. The results suggest that CRP may function as a potential therapeutic target for interrupting HBV replication as well as blocking HCC development.</p>