Ning G, Zhen LM, Xu WX, et al. - Researchers in their previous study identified rare missense mutations of complement component 2 (C2) to be linked with chronic hepatitis B (CHB). In the present work, they investigated the underlying role of C2 in CHB. Between January 2018 and January 2020, they obtained serum samples from 113 CHB patients and 30 healthy controls, and liver biopsy samples from 5 CHB patients and 3 healthy controls from the Third Affiliated Hospital of Sun Yat‐sen University. The influence of HBV infection on C2 expression was investigated using HepG2.2.15 and HepG2‐NTCP cells infected with HBV. The effect of IFN on C2 expression was assessed using IFN treated HepG2.2.15 cells. They constructed C2‐overexpressing or C2‐silencing in HepG2.2.15 cells to ascertain the effect of C2 on HBV infection. They observed significantly lower C2 expression in liver tissue and serum in CHB patients vs healthy controls, and significantly higher C2 expression in CHB patients with lower ALT, AST, Scheuer grade and stages vs CHB patients with higher ALT, AST, Scheuer grades and Scheuer stage. Further, HBV infection could reduce C2 expression by enhancing expression of Sp1 and limiting expression of HDAC4. Moreover, C2 could elevate the anti‐virus effect of IFN on HepG2.2.15 cells and also limit HBV replication in HepG2.2.15 cells by inhibition of p38‐MAPK signaling pathway. In conclusion, HBV may enhance viral persistence in CHB patients by reducing C2 expression.