FoxO4 inhibits HBV core promoter activity through ERK-mediated downregulation of HNF4α.

Hepatitis B virus (HBV) infection remains a global health problem, causing nearly one million deaths annually. Forkhead box O (FoxO) transcription factors play important roles in modulating diverse physiological processes. Recent studies show that FoxOs are involved in antiviral responses. In present investigation, we found that HBV induced significant down-regulation of FoxO4 protein, while had little effect on the expression of FoxO1 and FoxO3. Further study showed that FoxO4 displayed inhibitory effect on HBV transcription and replication both in vitro and in vivo. Mechanistically, it was found that FoxO4 exerted its anti-HBV activity by targeting HBV core promoter. Further, FoxO4 was revealed to inhibit HBV core promoter activity via downregulating hepatocyte nuclear factor-4α (HNF4α), and ERK signaling was required for FoxO4-mediated suppression of HNF4α and HBV core promoter activity. Together, these data indicated that FoxO4 displayed anti-HBV activity by suppressing HNF4α expression via activation of ERK pathway, and targeting FoxO4 might present as a novel therapeutic strategy against HBV infection.

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