Sesamin protects against Acetaminophen-induced nephrotoxicity by suppressing HMOX1-mediated apoptosis and ferroptosis

Acetaminophen (APAP) is a widely used antipyretic and analgesic agent, and acute exposure can lead to renal injury. Sesamin (Ses) is known for its various health benefits. However, it remains unclear whether Ses exerts a protective effect against APAP-induced kidney injury. In vivo, C57BL/6 mice were pretreated with Ses and injected intraperitoneally with APAP. In vitro, human kidney proximal tubule cells 2 were pretreated with Ses, and then models of kidney injury induced by APAP were established. Kidney damage was evaluated by morphological, inflammation, oxidative stress and protein analyzes. Ses significantly improved APAP-induced nephrotoxicity in vitro and in vivo models. Transcriptomic analysis revealed that the differentially expressed genes were enriched in ferroptosis and apoptosis signaling pathways, identifying heme oxygenase 1 (HMOX1) as a core protein. In the Ses-treated group, ferroptosis and apoptosis were significantly inhibited, while HMOX1 was effectively restored. In cell experiments, both the HMOX1 agonist hemin and Ses attenuated ferroptosis and apoptosis. HMOX1 inhibitor Zinc Protoporphyrin significantly eliminated the protective effect of Ses. Ses alleviates APAP-induced renal injury by mediating the inhibition of ferroptosis and apoptosis via HMOX1. This study provides a new strategy for the prevention and treatment of drug-induced renal injury.

对乙酰氨基酚（APAP）是广泛使用的解热镇痛剂，急性暴露可导致肾损伤。芝麻素（Ses）因其多种健康益处而为人所知，但尚不清楚其是否对APAP诱导的肾损伤具有保护作用。体内实验中，C57BL/6小鼠经Ses预处理后腹腔注射APAP；体外实验中，人类肾近端小管细胞2经Ses预处理后建立APAP诱导的肾损伤模型。通过形态学、炎症、氧化应激及蛋白质分析评估肾损伤程度。结果显示，Ses显著改善体外和体内模型中APAP诱导的肾毒性。转录组分析表明，差异表达基因富集于铁死亡（ferroptosis）和凋亡信号通路，其中血红素氧合酶1（HMOX1）被确定为核心蛋白。在Ses处理组中，铁死亡和凋亡受到显著抑制，而HMOX1表达得到有效恢复。细胞实验中，HMOX1激动剂血红素（hemin）与Ses均能减轻铁死亡和凋亡，而HMOX1抑制剂锌原卟啉（Zinc Protoporphyrin）则显著消除Ses的保护作用。综上，Ses通过介导HMOX1抑制铁死亡和凋亡，从而缓解APAP诱导的肾损伤，为药物性肾损伤的防治提供了新策略。