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.

Keywords: Cuproptosis; Ferroptosis; NAPCD; NETosis; PANoptosis.

Fig. 1

Crosstalk of ferroptosis, cuproptosis, NETosis, and PANoptosis in SARS-CoV-2 infection. Cuproptosis primarily occurs in the mitochondria, where Cu⁺ overload inhibits Fe-S clusters and disrupts the TCA cycle. Ferroptosis is triggered by ROS or the accumulation of Fe²⁺, which is promoted by inflammatory factors such as IL-6 that enhance TfR1 activity, while increase hepcidin activity to suppress ferroportin. NETosis is initiated by NETs formed by neutrophils, which release chromatin structures to neutralize viral particles. PANoptosis is a combination of apoptosis, necroptosis, and pyroptosis. Apoptosis can be triggered via the extrinsic pathway (death receptor pathway) or the intrinsic pathway (mitochondrial pathway). Necroptosis occurs when caspase-8 activity is inhibited by cFLIP and is mediated by phosphorylated RIPK1/RIPK3/MLKL. Pyroptosis is induced by the NLRP3 inflammasome via caspase-1, or by cytoplasmic LPS through caspase-4/5/11. The N protein, NSP6, and ORF7a of SARS-CoV-2 can activate the NF-κB pathway, releasing pro-inflammatory cytokines, including pro-IL-1β, pro-IL-18, procaspase-1 and NLRP3, contributing to pyroptosis. ACE2: angiotensin-converting enzyme 2; Gln, glutamine; GSH, glutathione; ROS: reactive oxygen species; Tf, transferrin; TfR1, transferrin receptor 1; TRADD, TNFR-associated death domain; FADD, Fas-associated death domain; RIPK 1/3, receptor-interacting serine‑threonine protein kinase 1/3; MLKL, mixed lineage kinase domain-like protein; cFLIP, cellular FLICE-inhibitory protein; APAF-1, apoptotic protease activating factor-1; Cytc, cytochrome c; N protein, nucleocapsid protein; NSP6, non-structural protein 6; ORF7a, open reading frame 7a; NLRP3, NOD-like receptor protein 3; ASC, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain; GSDMD, gasdermin D; N-GSDMD, N-terminal GSDMD; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor α; IL-6/18/1β, interleukin-6/18/1β; NET, neutrophil extracellular trap; MPO, myeloperoxidase; NE, neutrophil elastase.