Cepharanthine inhibits tick‑borne encephalitis virus infection through modulation of the stress and inflammation response

Cepharanthine is a potential candidate for developing antiviral agents against tick‑borne encephalitis virus (TBEV), which is a major cause of arboviral neuroinvasive diseases in humans. Cepharanthine is the only bisbenzylisoquinoline alkaloid for treating human diseases due to its unique pharmacological properties. Management of endoplasmic reticulum stress and inflammation response is implicated in therapeutic strategies for TBEV infection. The present study aimed to explore the antiviral efficacy and underlying mechanisms of cepharanthine against TBEV in human lung adenocarcinoma A549 cells and neuroblastoma SH‑SY5Y cells. In co‑treatment and pre‑treatment schemes, cepharanthine exhibited a potent inhibitory effect on TBEV propagation. The antiviral effect of cepharanthine was evidenced by a reduction in TBEV RNA replication, viral protein expression and infectious virus release. The levels of inflammatory cytokines, including tumor necrosis factor‑α, interleukin (IL‑) 1β and IL‑11, induced by TBEV infection were markedly decreased in A549 cells treated with cepharanthine. The induction of IL‑11 was impaired in infected SH‑SY5Y cells treated with cepharanthine. TBEV infection upregulated the expression of C/EBP homologous protein, which was downregulated by cepharanthine treatment. Phosphorylation of eukaryotic initiation factor 2α was enhanced upon cepharanthine treatment during TBEV infection. These in vitro results demonstrated that cepharanthine possesses anti‑TBEV efficacy and that modulation of the stress and inflammation response by cepharanthine may be involved in antiviral mechanisms. The results of the present study support further investigation of cepharanthine as an antiviral agent against TBEV.