Drug-induced liver injury (DILI) has a substantial impact on human health and is a major monetary burden on the drug development process. Presently, there is a lack of robust and analytically validated markers for predicting and early diagnosis of DILI. Sphingolipid metabolism and subsequent disruption of sphingolipid homeostasis has been documented to play a key role contributing to hepatocellular death and subsequent liver injury. A more comprehensive understanding of sphingolipid metabolism in response to liver toxicity has great potential to gain mechanistic insight into hepatotoxicity and define molecular markers that are responsible for hepatocyte dysfunction. Here, we present an analytical platform that provides multidimensional mass spectrometry-based datasets for comprehensive structure characterization of sphingolipids extracted from human primary hepatocytes (HPH) exposed to toxic levels of acetaminophen (APAP). Sphingolipid metabolism as measured by characterization of individual sphingolipid structure was sensitive to APAP toxicity displaying a concentration-dependent response. A number of sphingolipid structures were differentially expressed across varying APAP exposures highlighting the unique role sphingolipid metabolism has in response to hepatotoxicity and its potential use as a molecular marker in DILI.

药物性肝损伤（DILI）对人类健康具有重大影响，并且是药物开发过程中的主要资金负担。目前，缺乏可靠且经过分析验证的标记物来预测和早期诊断 DILI。鞘脂代谢和随后的鞘脂稳态破坏已被证明在导致肝细胞死亡和随后的肝损伤中发挥关键作用。更全面地了解肝毒性反应中的鞘脂代谢具有巨大的潜力，可以深入了解肝毒性的机制并定义导致肝细胞功能障碍的分子标记。在这里，我们提出了一个分析平台，该平台提供基于多维质谱的数据集，用于对从暴露于有毒水平的对乙酰氨基酚（APAP）的人原代肝细胞（HPH）中提取的鞘脂进行全面的结构表征。通过表征单个鞘脂结构来测量的鞘脂代谢对 APAP 毒性敏感，表现出浓度依赖性响应。许多鞘脂结构在不同的 APAP 暴露中存在差异表达，突显了鞘脂代谢在响应肝毒性方面的独特作用及其作为 DILI 分子标记的潜在用途。