Acetaminophen (APAP) is a commonly used pain and fever reliever but is also the most frequent cause of drug-induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, whereas mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wild-type and hepatocyte-specific SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of PBS or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, and inflammation were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by lower alanine aminotransferase and interleukin-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5′ AMP-activated protein kinase–unc-51-like autophagy activating kinase 1 signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury.

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SerpinA3N 在对乙酰氨基酚诱导的肝毒性中的潜在作用

对乙酰氨基酚 (APAP) 是一种常用的止痛和退烧药，但也是药物性肝损伤的最常见原因。有关对乙酰氨基酚毒性的机制已得到充分证明，而肝毒性机制尚未得到充分确立。丝氨酸（或半胱氨酸）肽酶抑制剂，进化枝 A，成员 3N (SerpinA3N)，一种丝氨酸蛋白酶抑制剂，在肝脏中合成，但 SerpinA3N 在 APAP 诱导的肝损伤中的作用尚不清楚。野生型和肝细胞特异性 SerpinA3N 敲除 (HKO) 小鼠腹膜内注射单剂量 PBS 或 APAP (400 mg/kg) 12 小时，并评估肝损伤、细胞死亡和炎症的标志物。在 APAP 过量的小鼠中，SerpinA3N 表达高度诱导。SerpinA3N HKO 小鼠的肝损伤和坏死减少，表现为丙氨酸氨基转移酶和白细胞介素 6 水平降低，同时炎症细胞因子受到抑制，中性粒细胞浸润减少。减少的氧化应激与增强的抗氧化酶能力有关。总之，肝细胞 SerpinA3N 缺乏通过改善炎症和调节 5' AMP 激活的蛋白激酶-unc-51 样自噬激活激酶 1 信号通路来减少 APAP 诱导的肝损伤。我们的研究为 SerpinA3N 在 APAP 诱导的肝损伤中的潜在作用提供了新的见解。总之，肝细胞 SerpinA3N 缺乏通过改善炎症和调节 5' AMP 激活的蛋白激酶-unc-51 样自噬激活激酶 1 信号通路来减少 APAP 诱导的肝损伤。我们的研究为 SerpinA3N 在 APAP 诱导的肝损伤中的潜在作用提供了新的见解。总之，肝细胞 SerpinA3N 缺乏通过改善炎症和调节 5' AMP 激活的蛋白激酶-unc-51 样自噬激活激酶 1 信号通路来减少 APAP 诱导的肝损伤。我们的研究为 SerpinA3N 在 APAP 诱导的肝损伤中的潜在作用提供了新的见解。