Exploring the Potential Value of Drugs Targeting Cellular Redox for the Treatment of Diseases Associated with KSHV Infection

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a pathogen associated with Kaposi's sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSassociated inflammatory cytokine syndrome malignancies. Similar to other gamma-herpesviruses, KSHV exhibits both latent and lytic phases. The genes expressed during these phases contribute to maintaining viral infection, promoting the survival of infected cells, and driving tumor development. Redox homeostasis is a central component in the regulation of cell proliferation, apoptosis, and immune response. The delicate balance between oxidative systems (reactive oxygen species and reactive nitrogen species) and antioxidant systems (GSH, thioredoxin, Nrf2, etc.) is crucial for viral replication and the remodeling of the tumor microenvironment. KSHV alters the host redox network through multiple mechanisms. The latent protein promotes Nrf2 nuclear translocation, which enhances antioxidant defenses and protects infected cells from ROS damage. Additionally, the cleavage protein vGPCR activates NADPH oxidase (NOX) to induce a reactive oxygen species burst, promoting angiogenesis and amplifying inflammatory signals. Therefore, an in-depth analysis of the KSHV-host redox interaction network and the development of intervention strategies targeting viral redox regulatory nodes are expected to enable precise antiviral and antitumor therapies. The review highlights the potential of redox targets as therapeutic agents for KSHV-associated diseases. It summarizes potential drug molecules and targets that achieve survival inhibitory effects by disrupting redox homeostasis in the KSHV host.