25-Hydroxycholesterol Restricts Japanese Encephalitis Virus via Metabolic Suppression of the SREBP2-Mediated Signaling Axis.

Host lipid metabolism is a critical determinant of viral pathogenesis. Although the interferon-inducible cholesterol 25-hydroxylase (CH25H) typically acts as a broad-spectrum antiviral protein, its expression and regulatory patterns during Japanese Encephalitis Virus (JEV) infection display unique features. Here, we demonstrate that 25-hydroxycholesterol (25HC), the product of CH25H, potently inhibits JEV proliferation by suppressing SREBP2 activation. Distinct from the majority of viral infections that induce CH25H upregulation, JEV infection elicits a transient reduction in CH25H abundance immediately after infection, coupled with a persistent elevation in SREBP2 expression. This inverse correlation suggests that JEV actively suppresses the CH25H-mediated metabolic checkpoint to maintain a cholesterol-synthetic environment favorable for replication. By pharmacologically simulating the activity of 25HC, we further verify that targeting the SREBP2 signaling axis can efficiently counteract this virally induced metabolic reprogramming. Our study identifies CH25H downregulation and concomitant SREBP2 activation as a key metabolic signature of JEV pathogenesis.