Peroxisome dynamics during HSV-1 life cycle in hiPSC-derived neurons

Over the past years, Herpes Simplex Virus type 1 (HSV-1) has been increasingly implicated in the progression of Alzheimer’s Disease (AD). Experimental evidence indicates that HSV-1 infection promotes pathological accumulations of phosphorylated tau and beta-amyloid, two hallmarks of AD. However, little is known about the effects of HSV-1 on peroxisomes, which have been recently associated to progression of AD and are implicated in essential neuronal functions such as beta-oxidation, redox balance, and lipid biosynthesis. Given also the demonstrated role of peroxisomal metabolism in viral infections, this study aimed to elucidate how HSV-1 infection, including latency and reactivation, influences peroxisomal dynamics and metabolism in neuronal systems. Using a combination of SH-SY5Y neuroblastoma cells, hiPSC-derived neurons, and cortical brain organoids, this work demonstrates that HSV-1 infection induces a robust increase in peroxisome number and transcriptional upregulation of key biogenesis genes (PEX13, PEX14, and PEX19). Pharmacological modulation experiments revealed that peroxisome proliferation enhances viral replication, indicating that HSV-1 actively exploits these organelles to support its life cycle. Additionally, lipidomic profiling further uncovers the functional role of peroxisomes in viral replication. A selective enrichment of plasmalogen lipids (pPE and pPC) was observed in SH-SY5Y cell, and the infection of a plasmalogen biosynthetic enzyme (AGPS)-deficient cells exhibited reduced viral replication, further underlying the role that plasmalogen plays in HSV-1 infection. Instead, mature neurons, which possess high basal plasmalogen levels, did not show further induction of this pathway, suggesting viral utilization of existing plasmalogen lipid pools. In brain organoids, peroxisomal remodeling was observed upon viral reactivation but not during latency, implying that recurrent HSV-1 reactivation may chronically disrupt peroxisomal and lipid homeostasis. Collectively, these findings identify peroxisomes and plasmalogen metabolism as critical components of HSV-1 infection. Far from being passive organelles, they emerge as metabolic hubs actively hijacked by the virus. By demonstrating that HSV-1 induces peroxisome biogenesis and modulates lipid metabolism, this work uncovers an unexplored layer of virus-host interaction in neuronal models. Overall, it provides a mechanistic framework for understanding how recurrent HSV-1 infection may progressively compromise neuronal health through chronic metabolic remodeling, potentially linking viral persistence to neurodegenerative processes.