Thrombopoietin Mitigates Neuronal Death by Enhancing Mitophagy and Suppressing NLRP3 Inflammasome Activation Under Oxygen-Glucose Deprivation Conditions

Thrombopoietin (TPO), a principal hematopoietic cytokine, regulates the development and proliferation of megakaryocytes and platelets. Our previous research demonstrated TPO‘s neuroprotective role against hypoxic-ischemic brain injury in rats. Yet, the underlying mechanisms remain unclear. This study reveals that A20 (Tumor necrosis factor alpha-induced protein 3, Tnfaip3) significantly contributes to TPO‘s neuroprotective effect by enhancing mitophagy in neurons. TPO reduces cell death under oxygen-glucose deprivation (OGD) conditions. Mechanistically, TPO induces the TNF-α and NF-κB signaling pathways to increase A20 expression, thereby promoting mitophagy, diminishing ROS production, and stabilizing mitochondrial membrane potential (MMP). A20 maintains mitochondrial dynamics and mitigates OGD-induced excessive mitochondrial fission. Furthermore, A20 suppresses NLRP3 inflammasome activation by enhancing mitophagy. This study elucidates a novel mechanism of TPO‘s neuroprotection, distinct from its hematological effects, supporting its potential therapeutic application in treating neurological injuries.