The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions.

Dengue virus (DENV) is the most prevalent arthropod-borne flavivirus and imposes a significant healthcare threat worldwide. At present no FDA-approved specific antiviral treatment is available, and the safety of a vaccine against DENV is still on debate. Following its entry into the host cell, DENV takes advantage of the cellular secretory pathway to produce new infectious particles. The key organelle of the host cell in DENV infections is the endoplasmic reticulum (ER) which supports various stages throughout the entire life cycle of flaviviruses. This review delves into the intricate interplay between flaviviruses and the ER during their life cycle with a focus on the molecular mechanisms underlying viral replication, protein processing and virion assembly. Emphasizing the significance of the ER in the flavivirus life cycle, we highlight potential antiviral targets in ER-related steps during DENV replication and summarize the current antiviral drugs that are in (pre)clinical developmental stage. Insights into the exploitation of the ER by DENV offer promising avenues for the development of targeted antiviral strategies, providing a foundation for future research and therapeutic interventions against flaviviruses.