Protective Effects of Cordycepin against Oxaliplatin-Associated Drug-Induced Fatty Liver Disease and Preliminary Mechanistic Insights

Oxaliplatin (OXA) is a chemotherapeutic agent used to treat multiple malignancies. Although it predominantly causes hepatic sinusoidal obstruction syndrome, it also induces drug-induced fatty liver disease (DIFLD) via lipid metabolic dysregulation and oxidative stress, which persists post-cessation, impairing long-term prognosis. Therefore, precise histopathological classification and targeted hepatoprotective interventions are crucial. Currently, no well-established preventive or therapeutic strategies for OXA-associated DIFLD exist. Cordycepin, a natural compound with established antihyperlipidemic and antioxidant properties, has not been studied for its protective effects against OXA-induced DIFLD. This study aimed to establish an acute OXA-induced DIFLD mouse model and evaluate the protective effects and underlying mechanisms of cordycepin intervention against OXA-induced DIFLD. An acute OXA-induced DIFLD model was established by administering 8 mg/kg OXA intraperitoneally daily for 3 days. Hepatic histopathology was assessed using hematoxylin and eosin and oil red O staining. Serum alanine aminotransferase, aspartate aminotransferase, hepatic and serum lipids (triglycerides, total cholesterol, and low-density lipoprotein, and oxidative stress markers (superoxide dismutase, malondialdehyde, and glutathione peroxidase were also measured. Non-targeted metabolomics and data-independent acquisition-based proteomics identified differential metabolites and proteins, followed by bioinformatic analysis. OXA significantly induced hepatic injury, steatosis, and oxidative stress, all of which were markedly attenuated by cordycepin treatment. Integrative metabolomic and proteomic analyses revealed that cordycepin modulated arginine biosynthesis and bile secretion pathways, downregulated oxoglutaric acid, and alleviated hepatotoxicity by regulating lipid metabolism and mitigating oxidative stress. This study demonstrated the efficacy of cordycepin against OXA-induced DIFLD and elucidated its underlying mechanisms, offering a novel therapeutic strategy and scientific basis for the precise management of OXA-associated hepatic injury.

奥沙利铂（Oxaliplatin, OXA）是一款用于治疗多种恶性肿瘤的化疗药物。尽管其主要引发肝窦阻塞综合征，同时可通过脂质代谢失调与氧化应激诱发药物性脂肪性肝病（drug-induced fatty liver disease, DIFLD），且该病变在停药后仍持续存在，损害患者长期预后。因此，精准的组织病理学分类与针对性肝保护干预措施至关重要。目前尚无针对奥沙利铂相关药物性脂肪性肝病的成熟防治策略。

冬虫夏草素（cordycepin）是一种已被证实具有降血脂与抗氧化特性的天然化合物，目前尚未有研究探讨其对奥沙利铂诱导的药物性脂肪性肝病的保护作用。

本研究旨在构建奥沙利铂诱导的急性药物性脂肪性肝病小鼠模型，并评估冬虫夏草素干预对该模型的保护作用及其潜在机制。实验通过每日腹腔注射8 mg/kg奥沙利铂、连续3天的方式，成功构建急性奥沙利铂诱导的药物性脂肪性肝病小鼠模型。采用苏木精-伊红染色与油红O染色评估肝脏组织病理学改变；检测血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶水平，肝脏与血清脂质（甘油三酯、总胆固醇、低密度脂蛋白）含量，以及氧化应激标志物超氧化物歧化酶、丙二醛、谷胱甘肽过氧化物酶水平。采用非靶向代谢组学与基于数据非依赖性采集（data-independent acquisition, DIA）的蛋白质组学技术鉴定差异代谢物与差异蛋白，并进行生物信息学分析。

结果显示，奥沙利铂可显著诱导肝损伤、脂肪变性与氧化应激，而冬虫夏草素治疗可显著缓解上述病理生理改变。整合代谢组学与蛋白质组学分析表明，冬虫夏草素可调控精氨酸生物合成与胆汁分泌通路，下调氧戊二酸水平，并通过调节脂质代谢、减轻氧化应激发挥肝保护作用。

本研究证实了冬虫夏草素对奥沙利铂诱导的药物性脂肪性肝病的保护作用，阐明了其潜在分子机制，为奥沙利铂相关性肝损伤的精准管理提供了新型治疗策略与科学依据。