ZNF33B Promotes Japanese Encephalitis Virus Infection by Regulating the Stability of M ⁶ A‐Modified Trim25 to Control the Autophagy Process

Japanese encephalitis virus (JEV) is a neurotropic flavivirus that causes a substantial threat to human health and livestock; however, the epitranscriptomic mechanisms that support its replication remain poorly defined. Here, we identify a proviral host factor C 2 H 2 zinc‐finger protein ZNF33B that promotes JEV infection through coupling N 6 ‐methyladenosine (m 6 A) RNA modification to autophagy regulation. Mechanistically, ZNF33B recruits METTL14 to stabilize the METTL3‐METTL14 methyltransferase complex, thereby increasing global m 6 A deposition. Multi‐omics analyses reveal that ZNF33B selectively binds m 6 A‐modified sites within the antiviral transcript Trim25 (c.1567 and c.1669 bp) to accelerate its decay. We further demonstrate that TRIM25 functions as an E3 ubiquitin ligase that catalyzes K48‐linked ubiquitination of ATG7 at lysines 389 and 423, leading to its proteasomal degradation and ultimately suppressing autophagic flux. In contrast, ZNF33B‐mediated Trim25 degradation counteracts its inhibitory effect on autophagy, creating a favorable environment for viral replication. In vivo, adeno‐associated virus (AAV)‐mediated ZNF33B delivery increases mouse brain m 6 A levels, decreases TRIM25 expression, elevates ATG7 abundance, exacerbates JEV‐induced neuropathology, and accelerates mouse mortality. Together, these findings reveal a previously uncharacterized ZNF33B‐m 6 A‐TRIM25‐autophagy axis that JEV hijacks to evade host antiviral responses, providing new insights into flaviviral pathogenesis and potential therapeutic targets.