Pannexin1: A potential therapeutic target for multi-organ ischemic diseases

Pannexins, a family of ATP-releasing channels, include Pannexin1 (Panx1), a widely expressed isoform found in almost all cell types. Panx1 participates in a wide array of physiological processes, including purinergic signaling, neuronal communication, vascular tone regulation, and immune responses. Recent studies have shown that the activation of Panx1 channels is closely related to ischemic diseases, and ischemia-reperfusion (IR) injury. When tissues and organs are stimulated by ischemia and hypoxia, Panx1 channels transition from closed to open, mediating ATP release through the Panx1-ATP-Purinergic Receptor (P2R) signaling axis, which can exacerbate tissue injury through independent or synergistic mechanisms, including regulation of inflammation, ferroptosis, oxidative stress, and mitophagy. This review, we systematically summarize the possible mechanisms involved in Panx1 and its activation process during ischemia, specifically in multi-organ (e.g., lung, brain, kidney, liver, heart). For better clinical translation, we summarize the Panx1 inhibitors and their pharmacological effects. The integration of multiple experiments revealed that Panx1 inhibitors can reduce ischemia-reperfusion injury (IRI) in organs by alleviating the inflammatory response, providing new therapeutic targets for studying ischemic diseases. However, Panx1 inhibitors are still in the preclinical research stage. The research and development challenges related to specificity, toxicity, and stability need to be overcome in the future. • A comprehensive examination of the activation and mechanism of action of Panx1 in ischemic diseases affecting the lung, brain, kidney, liver and heart. • The first systematic exploration of the Panx1-ATP-P2R signaling axis in multi-organ ischemic diseases. • A summary of the pharmacological effects and research advancements concerning specific inhibitors such as 10 Panx1, PxIL2P, and TAT-PanxY308, as well as various non-specific inhibitors. • An emphasis on the potential clinical value of Panx1 inhibitors in reducing damage from ischemic diseases and improving organ function.