The role of PANoptosis regulatory networks in acute neurological injury

Secondary injury following acute neurological insults-including stroke, spinal cord injury(SCI), traumatic brain injury(TBI), and subarachnoid hemorrhage(SAH)-is a major contributor to neuronal death and neuroinflammation; however, the complex molecular mechanisms driving these pathological processes remain poorly understood. The limited efficacy of traditional apoptosis-targeted therapies highlights the need to investigate alternative regulated cell death pathways governed by diverse and intricate regulatory networks. PANoptosis, an emerging form of inflammatory programmed cell death initially proposed to describe the crosstalk among apoptosis, pyroptosis, and necroptosis, is regulated by dynamic molecular complexes, such as the PANoptosome, which orchestrate multiple cell death-associated pathways and contribute to neuronal loss and the amplification of inflammatory responses. This review provides a comprehensive overview of the molecular mechanisms of PANoptosis and its functional roles in acute neurological injury, with a particular emphasis on its pathological regulatory networks associated with ischemic stroke and spinal cord injury. Furthermore, we highlight emerging therapeutic strategies targeting PANoptosis. Recent evidence has identified key molecular mediators, including Z-DNA-binding Protein 1 (ZBP1), receptor-Interacting Protein Kinase 1 (RIPK1), and TGF-β-Activated Kinase 1 (TAK1), which regulate PANoptosome assembly and downstream effector pathways, highlighting their potential as promising therapeutic targets. Inhibition of PANoptosis has been shown to markedly alleviate blood-brain barrier (BBB) disruption and neurological deficits. Additionally, this review addresses the translational challenges and future research directions in targeting PANoptosis, providing a theoretical basis for the development of multi-targeted neuroprotective strategies. FACTS: Facts: PANoptosis integrates pyroptosis, apoptosis, and necroptosis via PANoptosome-associated signaling. ZBP1, RIPK1, and TAK1 are key regulators of PANoptosis in acute neurological injury models. Inhibition of PANoptosis attenuates BBB disruption and improves functional recovery. OPEN QUESTIONS: How do PANoptosome subtypes differ among CNS cell types? Can PANoptosis‑specific biomarkers be validated for clinical use? What are the optimal multi‑target strategies for inhibiting PANoptosis without compromising immunity?