Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY–cAMP–PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY–PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.

溶酶体调节细胞代谢以维持细胞存活，但它们在急性代谢应激后决定神经元细胞命运的机制尚不清楚。富含神经元的溶酶体膜蛋白 LAMP2A 参与选择性分子伴侣介导的自噬和外泌体加载。这项研究表明，神经元 LAMP2A-溶酶体途径的异常会导致缺血性中风后的神经功能缺陷，并且这是 PANoptosis 样分子途径和神经炎症的早期诱导物，同时诱导缺血后 FADD、RIPK3 和 MLKL 的上调。定量蛋白质组学和药理学分析表明，急性代谢应激后，神经元 LAMP2A 通路诱导急性突触变性和 PANoptosis 样反应，涉及蛋白激酶 A (PKA) 信号传导下调。 LAMP2A 指导中风后腺苷酸环化酶 (ADCY) 的溶酶体降解，包括皮层神经元中的 ADCY1 和 ADCY3。中风后使用 cAMP 模拟物或 ADCY 激活剂治疗可挽救皮质神经元免受 PANoptosis 样反应和神经炎症的影响，这表明神经元 ADCY-cAMP-PKA 轴是缺血性中风后病理生理过程的上游阻滞剂。这项研究表明，神经元 LAMP2A-溶酶体通路通过下调 ADCY-PKA 信号级联，驱动大脑代谢应激后复杂的急性神经退行性和神经炎症反应，并强调了 PKA 信号诱导剂改善中风结局的治疗潜力。