Pannexin 1 Beyond the Plasma Membrane in Neuroinflammation: An Organelle-Centered Perspective and Therapeutic Opportunities.

Neuroinflammation drives the progression of diverse central nervous system (CNS) disorders. Classically, Pannexin 1 (Panx1) is characterized as a plasma membrane channel responsible for ATP efflux and purinergic signaling. However, this surface-restricted view limits our understanding of the profound intracellular metabolic and structural damage observed in neuroinflammatory cascades. In this review, we propose a conceptual shift regarding Panx1 function. Rather than acting merely as an ATP conduit, emerging evidence partially from peripheral models suggests Panx1 may operate as a potential node for inter-organelle crosstalk. Aberrant Panx1 activation is proposed to drive ionic and metabolic imbalances that compromise the integrity of mitochondria, the endoplasmic reticulum (ER), and lysosomes. By disrupting these critical communication networks, Panx1 is hypothesized to link localized cellular stress to regulated cell death (RCD) programs, including apoptosis, necroptosis, pyroptosis, parthanatos, ferroptosis, and PANoptosis. To mechanistically explore whether the organelle impairment is secondary to surface ionic shock or driven by direct intracellular channel activity, we propose a "dynamic spatiotemporal redistribution" hypothesis, suggesting that pathology may actively induce Panx1 internalization into deep endomembrane systems, although distinguishing this active shuttling from generalized passive intracellular trafficking remains a critical challenge. Finally, we translate this organelle-centric paradigm into future clinical perspectives, advocating a shift from indiscriminate channel pore blockade toward state-dependent, organelle-specific precision pharmacology. This review aims to re-examine Panx1 in neuroinflammation by transitioning its conceptual model from a simple membrane protein to a potential hub of inter-organelle crosstalk, which may open new avenues for development of precision neurotherapeutics targeting Panx1 for neuroinflammation.