PO.MCB09.02 · 分子与细胞生物学
通过MUFA耗竭破坏肿瘤脂质稳态驱动HCC细胞死亡
Disrupting tumor lipid homeostasis by MUFA depletion drives cell death in HCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：饱和脂肪酸与单不饱和脂肪酸之间的细胞平衡是肿瘤脂质代谢的一个决定性特征，其中SCD1通过产生MUFA充当关键调节因子。肝细胞癌中已记录到SCD1活性升高和MUFA积累，尽管限制MUFA合成的后果尚未完全阐明。
方法：在已建立的人类HCC细胞系和异种移植模型中评估了一种选择性SCD1抑制剂SSI-4。测量包括细胞活力、脂质组成分析，以及在分子和生化水平上对应激反应通路的表征。在体外和体内研究了MUFA耗竭的效应，重点关注ER应激、凋亡、铁死亡标志物和自噬诱导。
结果：SSI-4处理导致细胞MUFA含量显著降低和饱和脂肪酸库增加。由此产生的代谢应激与未折叠蛋白反应组分的激活、caspase介导的细胞死亡以及铁死亡相关基因的上调相关。甘油三酯和MUFA水平急剧下降，这经基于质谱的脂质组学证实。在PDX模型中肿瘤生长受到抑制，敏感细胞系中出现自噬通量的证据。反应的可变性突显了HCC的代谢异质性。
结论：靶向破坏MUFA生物合成给HCC细胞带来代谢脆弱性，引发膜改变并激活多种细胞死亡程序。这些发现建议进一步研究利用MUFA耗竭的代谢干预，并考虑根据脂质代谢表型对患者进行分层。
资助：本工作得到Mayo Clinic综合癌症中心、Mayo Clinic Jacksonville的Jay and Deanie Stein癌症研究职业发展奖，以及Mayo Clinic转化性肝胆癌SPORE P50CA210964职业提升计划（CEP）和佛罗里达州卫生部/佛罗里达癌症创新基金C25C23的支持。
查看英文原文 English abstract
Background: The cellular balance between saturated and monounsaturated fatty acids is a defining feature of tumor lipid metabolism, with SCD1 functioning as a key modulator through the production of MUFAs. Elevated SCD1 activity and MUFA accumulation have been documented in hepatocellular carcinomas, although the consequences of restricting MUFA synthesis have not been fully clarified.
Methods: A selective SCD1 inhibitor, SSI-4, was evaluated across established human HCC cell lines and xenograft models. Measurements included cell viability, lipid compositional analyses, and characterization of stress response pathways at both molecular and biochemical levels. The effects of MUFA depletion were studied in vitro and in vivo , with attention to ER stress, apoptosis, ferroptosis markers, and autophagy induction.
Results : SSI-4 treatment led to marked reduction in cellular MUFA content and an increase in saturated fatty acid pools. The resulting metabolic stress correlated with activation of unfolded protein response components, caspase-mediated cell death, and the upregulation of ferroptosis-associated genes. Triglyceride and MUFA levels declined precipitously, as confirmed by mass spectrometry-based lipidomics. Tumor growth was suppressed in PDX models and evidence of autophagic flux was apparent in sensitive cell lines. Variability in response highlights metabolic heterogeneity in HCC.
Conclusions: Targeted disruption of MUFA biosynthesis inflicts metabolic vulnerability on HCC cells, precipitating membrane alterations and activation of multiple cell death programs. These findings recommend further investigation into metabolic interventions exploiting MUFA depletion, with consideration for stratifying patients according to lipid metabolic phenotypes.
Funding: This work is supported by Mayo Clinic Comprehensive Cancer Center and the Jay and Deanie Stein Career Development Award for Cancer Research at Mayo Clinic Jacksonville and the Mayo Clinic Translational Hepatobiliary Cancer SPORE P 50CA210964 Career Enhancement Program (CEP) and Florida Department of Health/Florida Cancer Innovation Fund C25C23.
利益披露 Disclosure
J. J. Gleba, None.