Transcriptomic Insights into the Host Response to MPXV Infection in Human Neuronal Cells

The Monkeypox virus (MPXV) is a neurotropic zoonotic pathogen, as evidenced by neurological symptoms in patients and its demonstrated neuroinvasive potential in both in vitro and in vivo models. However, the host responses and mechanisms underlying MPXV-induced neural damage remain poorly understood. To address this gap, we performed transcriptomic profiling and functional validation across three human neuronal cell lines (U87MG, SH-SY5Y, and HMC3) to investigate MPXV-induced molecular alterations. Among these cell types, U87MG cells exhibited the most pronounced transcriptional changes. Specifically, MPXV infection activated the MAPK signaling pathway (ERK1/2 and p38) and elicited a strong pro-inflammatory response, characterized by elevated TNF-α, IL-16, IL-17, and IL-1β. In parallel, immune evasion signatures were detected, including upregulation of MOGS, DICER1, and VPS13A, along with downregulation of STAT1 and IFIT family genes. Notably, MPXV markedly suppressed ADAR1, a key RNA-editing enzyme essential for neural homeostasis and antiviral defense, thereby implicating ADAR1 dysregulation as a driver of virus-induced neuroinflammation and injury.