乙醛异丙酰肼（APAP）过量引起的大肝损伤与Toll样受体（TLRs）4和9介导的无菌炎症反应有关。 TLR依赖的信号与磷脂鞘氨醇3-激酶（PI3K）等其他胞内激酶存在交流。然而，PI3Kα在肝脏无菌炎症中的详细作用仍不明确。因此，本研究考察了新型PI3Kα抑制剂阿维利司他在APAP引起的肝脏无菌炎症模型中的效果。通过在APAP（500mg/kg，i.p.）中毒前2小时给予小鼠口服阿维利司他（5和10mg/kg），检测了其对APAP诱导的血清肝功能生物标志物和肝坏死炎症评分升高的影响。结果显示阿维利司他剂量依赖性地降低了APAP诱导的血清肝功能生物标志物升高和肝坏死炎症评分。阿维利司他还减弱了APAP诱导的肝细胞中剪切的半胱氨酸蛋白酶3和增殖细胞核抗原（PCNA）水平，作为凋亡和增殖的指标。机制上，阿维利司他通过关闭多种信号转导蛋白的激活，包括细胞外信号调节激酶（ERK）、c-Jun N末端激酶（JNK）、信号传导与转录激活因子3（Stat-3）、糖原合成激酶（GSK）-3β和核因子（NF）-κB，限制了APAP引起的体内炎症性肿瘤坏死因子（TNF）-α，白细胞介素（IL）-1β和IL-6的过度产生。阿维利司他还通过减少全身粒子/巨噬细胞集落刺激因子（GM-CSF）的释放，逆转了APAP引起的全身和肝脏抗炎性IL-10和IL-22水平异常，从而减弱了APAP引起的免疫细胞浸润肝脏的现象。总之，阿维利司他通过选择性调节PI3Kα活性可以抑制APAP引起的炎症反应和免疫细胞浸润。

The sterile inflammatory response mediated by Toll-like receptors (TLRs) 4 and 9 is implicated in the massive hepatic damage caused by acetaminophen (APAP)-overdose. There is a crosstalk between TLR-dependent signaling with other intracellular kinases like phosphatidylinositol 3-kinases (PI3Ks). Nevertheless, the detailed role of PI3Kα is still unknown in hepatic sterile inflammation. Accordingly, the effect of the novel PI3Kα inhibitor alpelisib was investigated in the setting of APAP-driven sterile inflammation in the liver. This was examined by pretreating mice with alpelisib (5 and 10 mg/kg, oral) 2 h before APAP (500 mg/kg, i.p.)-intoxication. The results indicated that alpelisib dose-dependently lowered APAP-induced escalation in serum liver function biomarkers and hepatic necroinflammation score. Alpelisib also attenuated APAP-induced rise in cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in the liver hepatocytes, as indices for apoptosis and proliferation. Mechanistically, inhibition of PI3Kα by alpelisib limited APAP-induced overproduction of the pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the blood circulation via switching off the activation of several signal transduction proteins, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription-3 (Stat-3), glycogen Synthase Kinase (GSK)-3β and nuclear factor (NF)-κB. Alpelisib also impaired APAP-instigated immune cell infiltration in the liver via reducing systemic granulocyte/macrophage-colony stimulating factor (GM-CSF) release and reversed APAP-induced abnormalities in the systemic and hepatic levels of the anti-inflammatory IL-10 and IL-22. In conclusion, selective modulation of the PI3Kα activity by alpelisib can hinder the inflammatory response and infiltration of immune cells occurring by APAP-hepatotoxicity.Copyright © 2023 Shaker, Gomaa, Hazem, Abdelgawad, El-Mesery and Shaaban.