Lesser-known non-apoptotic programmed cell death in viral infections.

Abstract

Non-apoptotic programmed cell death (NAPCD) represents a diverse set of cell death mechanisms that differ from classical apoptosis and have recently gained attention in the context of viral infections. This review focuses on four key NAPCD types, including ferroptosis, cuproptosis, NETosis (neutrophil extracellular trap formation), and PANoptosis (a combination of pyroptosis, apoptosis, and necroptosis), and summarizes their distinct molecular pathways and roles during viral infections. We emphasize their functional relevance in SARS-CoV-2 infection, revealing how they significantly impact viral replication, host immune responses, and tissue damage. Furthermore, we explore the interaction between NAPCDs and specific immune responses. Specifically, ferroptosis influences macrophage polarization. Cuproptosis activates innate immunity via the cGAS-STING pathway. NETosis contributes to Th17 responses, and PANoptosis interacts with Th1, Th22, and Thαβ pathways. Understanding the interplay among these cell death pathways provides new insights into host-virus dynamics and uncovers potential therapeutic targets for viral diseases.