Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in -overexpression (-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the behavior of S14 significantly. By encapsulation with micelles, the AUC, half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

中文翻译：

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一种新型海洋源性抗急性肾损伤过氧化物酶1药物及其基于ADME优化的纳米递送策略

急性肾损伤（AKI）的治疗策略不足，需要针对其发病机制进行精准治疗。这项研究揭示了海洋源性抗 AKI 药物、杀粉粉素糖苷 S14 靶向过氧化还原蛋白 1 (PRDX1) 的新机制。通过与 PRDX1 的 Cys83 结合并增强其过氧化物酶活性，S14 可以有效减轻 - 过度表达 (-OE) 小鼠的肾损伤。此外，S14还增加PRDX1核转位并直接激活Nrf2/HO-1/NQO1途径以抑制ROS产生。由于S14的成药性有限、生物利用度低(2.6%)和肾脏分布差，因此构建了pH敏感的肾脏靶向十二胺-壳聚糖纳米颗粒系统来负载S14，用于AKI的精准治疗。L-丝氨酸与壳聚糖的结合赋予肾损伤分子 1 (Kim-1) 过表达细胞特异性。所开发的S14纳米药物通过显着改善S14的行为而表现出更高的治疗效率。通过胶束封装，S14 的 AUC、半衰期和肾分布分别增加 2.5 倍、1.8 倍和 3.1 倍。提高S14纳米药物成药性的主要因素包括较低的代谢消除率和UDP糖基转移酶（UGT）介导的生物转化。总之，本研究确定了海洋源性抗 AKI 药物的新治疗靶点，同时通过纳米技术增强其 ADME 特性和成药性，从而推动 AKI 海洋药物开发的进步。