PANoptosis emerges as a major integrated cell-death response driven by excitotoxicity, inflammation, and mitochondrial dysfunction. During ischemia and reperfusion, excessive glutamate release overstimulates NMDA receptors, causing massive Ca²⁺ influx into neurons and mitochondrial overload. This leads to mitochondrial permeability transition pore opening, cytochrome c release, and ROS generation, priming the cell for apoptosis and amplifying inflammatory signaling. Meanwhile, damage-associated molecular patterns generated during stroke activate ZBP1, which in turn triggers assembly of the PANoptosome, a multiprotein platform containing ASC, Caspase-8, and the RIP1–RIP3 complex. Once active, the PANoptosome coordinates apoptosis (via Caspase-8 and Caspase-3), pyroptosis (via ASC-mediated Caspase-1 activation leading to Gasdermin-D pores and cytokine release), and necroptosis (via RIP1–RIP3–MLKL–mediated membrane rupture). In stroke, this convergence of mitochondrial injury, Ca²⁺ dysregulation, and innate immune activation makes PANoptosis a potent driver of neuronal loss and secondary inflammation, contributing to the worsening of tissue damage beyond the initial ischemic event.

PANoptosis References