Letter to the Editor: Expanding the VZV epigenetic-immune framework: from mechanisms to precision medicine

Dear Editor, We read with great interest the review article by Peng et al[1] titled “Epigenetic Regulation of Varicella-Zoster Virus Infection: A Systematic Synthesis of Mechanisms.” Through bibliometric analysis, their study identifies a significant gap in epigenetic research on herpesviruses and emphasizes the pressing need for clinical translation. The authors provide a systematic outline of the bidirectional regulatory network between epigenetic mechanisms and immune modulation, which significantly advances our understanding of varicella-zoster virus (VZV) latency and reactivation. We commend this contribution and would like to suggest that integrating non-coding RNA (ncRNA), deciphering ganglionic microenvironment heterogeneity, and elucidating the role of host genetic background could extend this framework into a more individualized and predictive roadmap for precision medicine. This commentary adheres to the TITAN guidelines[2]. Firstly, this review systematically describes transcriptional regulation, DNA methylation, and histone modification (Sections 5.2–5.3). However, the role of ncRNAs as key regulators in epigenetic control during VZV infection has not been fully explored. Studies suggest that VZV-encoded small non-coding RNAs may antisense-regulate latency-associated transcripts[3]. Including this regulatory layer might offer a more comprehensive mechanistic understanding and provide new targets for innovative RNA interference-based therapies. We believe this could further strengthen the overall framework. Secondly, the anatomical microenvironment of VZV latency is heterogeneous. The trigeminal ganglion and dorsal root ganglion differ significantly in developmental origin and immune composition[4,5]. It would be beneficial to explore how these functional niche differences might contribute to the higher complication risk of herpes zoster ophthalmicus compared to trunk zoster. Applying advanced techniques such as spatial transcriptomics and single-cell sequencing could help uncover the mechanistic differences that underlie distinct clinical phenotypes. This line of investigation could further refine our understanding of VZV reactivation and its varied clinical presentations. Thirdly, while the review notes that immunosuppression elevates reactivation risk, it does not fully explain the marked interindividual differences in outcomes under similar conditions. This highlights the importance of host genetic background as a factor. Genome-wide association studies have identified polymorphisms in HLA and other immune-related gene loci associated with VZV susceptibility[6]. Additionally, research suggests that genetic variants might influence immune responses to VZV by modulating the epigenetic accessibility of immune genes, potentially altering the threshold for immune surveillance[7]. Integrating this dimension would significantly improve the framework’s individualized risk-prediction value. Finally, as research on VZV advances, we believe that intervention strategies need to evolve to become more personalized and timely. Potential strategies include long-term suppression for genetically high-risk individuals, short-course blockade during early reactivation, and combined approaches using ganglion-specific delivery and ncRNA targeting. The ultimate goal is a precision medicine paradigm of “the right time, the right site, and the right individual.” In conclusion, we commend the authors for their excellent work in providing a critical foundation for future research in this area. We look forward to the continued advancement of the field and the potential for further refinement of this important framework. The article was written in accordance with the TITAN Guidelines 2025.