Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.

中文翻译：

---

抗炎硫酸乙酰肝素的设计可预防对乙酰氨基酚引起的急性肝衰竭。

在美国和欧洲，对乙酰氨基酚/扑热息痛 (APAP) 过量是药物引起的急性肝衰竭 (ALF) 的主要原因。该疾病的进展归因于高迁移率族蛋白 1 (HMGB1) 的释放以及与晚期糖基化终末产物 (RAGE) 受体的相互作用诱导的无菌炎症。非常需要一种特异性、有效且安全的方法来中和 HMGB1 的促炎活性。在这里，我们发现硫酸乙酰肝素 (HS) 十八糖（18-mer-HP 或保肝 18-mer）通过靶向 HMGB1/RAGE 轴显示出有效的保肝作用。小鼠和人类过量服用 APAP 后会释放内源 HS 蛋白多糖 syndecan-1。此外，纯化的 syndecan-1（而非 syndecan-1 核心蛋白）与 HMGB1 结合，表明 HMGB1 与 syndecan-1 的 HS 多糖侧链结合。最后，我们比较了 18-mer-HP 和 N-乙酰半胱氨酸之间的保护作用，这是治疗 APAP 过量的护理标准。我们证明，在致死剂量的 APAP 3 小时后施用 18-mer-HP 具有完全保护作用；然而，N-乙酰半胱氨酸的治疗失去了保护作用。因此，对于晚期就诊的患者，18-mer-HP 可能比 N-乙酰半胱氨酸具有潜在的治疗优势。合成 HS 为治疗 APAP 诱导的 ALF 提供了一种潜在的方法。