Cell death network regulation in HSV infection: immune evasion versus host defense

Herpes simplex virus type 1 (HSV-1) causes prevalent infections ranging from orolabial lesions to keratitis and encephalitis, with virus-host interplay around cell death pathways critically determining disease outcomes. This review systematically examines how HSV-1 dynamically manipulates programmed cell death processes-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-through multiple viral proteins to evade immune clearance, facilitate replication, or maintain latency. Concurrently, host DNA sensors such as AIM2 and IFI16 activate inflammasomes and the PANoptosome to trigger coordinated cell death that restricts viral spread; imbalances in this bidirectional regulation exacerbate tissue damage in skin, cornea, and central nervous system, driving neuroinflammation and blood-brain barrier disruption. Elucidating these mechanisms not only uncovers novel principles of HSV-1 pathogenesis and immune evasion but also informs antiviral therapies and the rational design of oncolytic HSV-1 vectors.