He Tianmu, Lin Kexin, Xiong Lijuan, Zhang Wen, Zhang Huan, Duan Cancan, Li Xiaofei, Zhang Jianyong
School of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China.
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550014, China.
J Pharm Anal. 2025 Jul;15(7):101210. doi: 10.1016/j.jpha.2025.101210. Epub 2025 Jan 24.
Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids . The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.
斑蝥素（CTD）是一种临床上用于治疗多种肿瘤的天然化合物，但由于急性肾损伤（AKI）而受到限制。然而，AKI的主要原因及其潜在机制仍有待阐明。在小鼠中进行3天的CTD（1.5mg/kg）灌胃后，通过病理评估检测血清肌酐（SCr）和血尿素氮（BUN）。基于超高效液相色谱-串联质谱（UPLC-MS/MS）的肾脏脂质组学用于研究CTD暴露后小鼠的脂质紊乱。然后，基于基质辅助激光解吸/电离质谱成像（MALDI-MSI）的空间代谢组学用于检测肾脏脂质的空间分布。进行综合分析以揭示空间脂质紊乱机制并验证关键脂质。结果表明，SCr和BUN水平升高，小鼠肾脏出现肾小管坏死，导致CTD诱导的AKI中的急性肾小管坏死（ATN）。然后，脂质组学结果显示，CTD暴露后，232种差异脂质代谢物和11条途径（包括甘油磷脂（GP）和鞘脂（SL）代谢）受到破坏。空间代谢组学显示55种空间差异脂质代谢物和9条代谢途径受到干扰。随后，综合分析发现GP代谢在肾皮质和髓质中受到刺激，而SL代谢在肾皮质中受到抑制。上调的溶血磷脂酰胆碱（LysoPC）（18:2(9Z,12Z)）、LysoPC（16:0/0:0）、甘油磷酸胆碱，以及下调的鞘磷脂（SM）（d18:0/16:0）、SM（d18:1/24:0）和SM（d42:1）是关键的差异脂质。其中，LysoPC（16:0/0:0）在CTD组中以1.1196μg/mL的浓度增加，这加剧了CTD诱导的人肾2（HK2）细胞中的ATN。在小鼠和HK2细胞中进行CTD干预后，LysoPC酰基转移酶受到抑制，胆碱磷酸转移酶1（CEPT1）被激活。CTD通过激活肾皮质和髓质中的GP代谢并抑制SL代谢来诱导ATN，从而导致AKI，LysoPC（16:0/0:0）、LysoPC酰基转移酶和CEPT1可能是治疗靶点。
