Cepharanthine hydrochloride alleviates herpesvirus encephalitis by inhibiting Nrf2 degradation.

Herpes simplex virus type 1 (HSV-1) infection can induce herpes simplex encephalitis (HSE), a life-threatening neurological disorder characterized by active viral replication within the central nervous system accompanied by excessive neuroinflammatory responses. Cepharanthine hydrochloride (CH) is a natural bisbenzylisoquinoline alkaloid with diverse pharmacological activities. CH was evaluated for its antiviral and anti-inflammatory activities against HSV-1 infection. In microglia, CH markedly inhibited viral replication and suppressed STING-NF-κB signaling, thereby reducing HSV-1-associated neuroinflammation. During HSV-1 infection, CH binds to Nrf2, disrupting Keap1-Nrf2 interaction and subsequent ubiquitination. This hindered Nrf2 degradation and attenuated STING activation. In an HSE mouse model, CH significantly reduced viral loads in brain tissue, improved survival rates, prevented weight loss, and alleviated neurological symptoms. Furthermore, CH promoted the accumulation of Nrf2 and inhibited the STING-NF-κB signaling pathway in vivo. Collectively, these results indicate that CH represents a potential antiviral strategy for HSE.