背景:靶向铁凋亡已被确定为开发癌症疗法的有希望的方法。单不饱和脂肪酸(MUFA)是一种在抑制铁死亡中起关键作用的脂质。Ficolin3(FCN3)是补体系统的组成部分,在凝集素途径中充当针对病原体的识别分子。最近的研究报道FCN3对某些肿瘤的进展具有抑制作用。然而,FCN3是否可以调节脂质代谢和铁凋亡仍在很大程度上未知。
方法:细胞活力,BODIPY-C11染色,进行MDA测定以检测铁细胞凋亡。利用原发性肝细胞癌(HCC)和异种移植模型来研究FCN3对体内HCC发展的影响。进行代谢组学分析以评估细胞内和HCC肝内脂质水平的变化。
结果:我们的研究阐明了补体系统组成部分FCN3的表达大幅下降,导致MUFA在人HCC标本中积累,从而显着促进铁凋亡抗性。FCN3的过表达有效地使HCC细胞对铁凋亡敏感,导致抑制原发性HCC和皮下HCC异种移植物的肿瘤发生和进展。机械上,FCN3直接与胰岛素受体β(IR-β)及其前体形式(pro-IR)结合,抑制pro-IR裂解和IR-β磷酸化,最终导致IR-β失活。IR-β的失活抑制了固醇调节元件结合蛋白1c(SREBP1c)的表达,随后抑制与从头脂肪生成(DNL)和脂质去饱和相关的基因的转录,并因此下调细胞内MUFA水平。
结论:这些发现揭示了FCN3增强HCC细胞对铁凋亡的敏感性的一种新的调节机制,这表明靶向FCN3诱导的铁凋亡是肝癌治疗的一个有希望的策略。
BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown.
METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels.
RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels.
CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.