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Abstract

Virus-induced inflammation and programmed cell death (PCD) are critical antiviral defenses, prompting viruses like respiratory syncytial virus (RSV) to develop PCD regulation mechanisms. Here, we demonstrate that RSV orchestrates the temporal and sequential regulation of distinct PCD pathways in human macrophages to optimize replication and dissemination. During early stages of infection, RSV activates the PI3K-Akt pathway to induce cFLIP expression, effectively suppressing TNF-driven extrinsic apoptosis. Simultaneously, viral degradation of ZDHHC9 prevents GSDMD-mediated pyroptosis downstream of NLRP3 activation, thereby sustaining an intracellular environment permissive to viral propagation. In contrast, following the completion of replication, RSV subverts caspase-1 signaling to trigger the intrinsic apoptotic cascade via the Casp-1–BID–APAF1–Casp-9 axis, and subsequently promotes GSDME-mediated secondary pyroptosis. This late-stage PCD reprogramming enables synchronized release of virions and pro-inflammatory cytokines, exacerbating pulmonary pathology. These findings delineate a temporally resolved strategy by which RSV balances early immune evasion with subsequent viral dissemination and immunopathology, and identify discrete stage-specific molecular targets for therapeutic intervention in RSV-induced lung disease.