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-a, IL-16, IL-17, and IL-1ß. 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. Overall design: Building on these findings, network and drug-target analyses identified core transcriptional regulators (e.g., EGR, ZBTB7A, POU2F2) and candidate compounds modulating ADAR1. Consistently, in human iPSC-derived astrocytes, MPXV triggered inflammatory and apoptotic phenotypes accompanied by ADAR1 downregulation. Crucially, functional assays demonstrated that two ADAR-targeting compounds—Prosaptide and Neuropeptide Head Activator—effectively suppressed MPXV replication. In conclusion, our study provides the first integrative transcriptomic and functional characterization of MPXV infection in neuronal cells, and identifies ADAR1 as a pivotal mediator of MPXV-induced neuropathogenesis and a promising therapeutic target.