Exosome‐Mediated Signaling Amplification in Lytic Cell Death: Molecular Coupling, Pathway Activation and Therapeutic Targeting

ABSTRACT

Extracellular vesicles (EVs), including endosome‐derived exosomes and other EV subtypes, mediate intercellular communication through regulated cargo transfer. Lytic cell death (LCD), including pyroptosis, necroptosis, and ferroptosis, is traditionally linked to inflammation via membrane rupture and passive release of damage‐associated molecular patterns (DAMPs). However, emerging evidence indicates that LCD execution is mechanistically coupled to exosome biogenesis prior to terminal lysis. Gasdermin D (GSDMD)‐ or mixed lineage kinase domain‐like protein (MLKL)‐mediated membrane permeabilization generates a transient sub‐lytic state, maintained by endosomal sorting complex required for transport III (ESCRT‐III)–dependent membrane repair, that preserves endosomal trafficking and supports exosome release. These EV populations are enriched in damage‐associated proteins, mitochondrial nucleic acids and oxidized lipids, and can activate inflammatory and innate immune signaling pathways in recipient cells. Thus, exosomes convert cell death–associated signals into transferable signaling units that propagate inflammation. We propose an integrated LCD–exosome signaling axis and discuss potential therapeutic strategies targeting cell death execution, vesicle biogenesis and downstream pathway activation.