Ferroptosis,以铁介导的非凋亡性细胞死亡和脂质氧化还原代谢改变为特征,已经成为涉及各种细胞功能的关键过程,包括癌症.Aurantio‑obtusin(AO),从决明子精液(CassieobtusifoliaL.或决明子的干燥成熟种子)衍生的生物活性化合物,具有抗高脂血症和抗氧化特性;然而,据我们所知,AO对肝癌细胞的影响尚不清楚.细胞计数试剂盒-8,EdU染色和迁移测定用于评估AO的抗肝癌活性。测量谷胱甘肽过氧化物酶4蛋白和脂质过氧化的细胞内水平作为铁凋亡状态的指标。免疫组织化学分析,进行了生物信息学分析和蛋白质印迹,以评估硬脂酰辅酶A去饱和酶1(SCD1)与铁凋亡诱导剂联合用于肝癌个性化治疗的潜力。本研究表明,AO在体外和体内显着抑制肝癌细胞的增殖。机械上,AO抑制AKT/哺乳动物雷帕霉素靶蛋白(mTOR)信号,抑制固醇调节元件结合蛋白1(SREBP1)的表达,和下调脂肪酸合成酶的表达,从而抑制从头脂肪酸合成。进一步的研究表明,AO通过核因子红细胞2相关因子2/血红素加氧酶-1途径抑制谷胱甘肽过氧化物酶4蛋白的表达,诱导肝癌细胞的铁凋亡,同时通过AKT/mTOR/SREBP1途径抑制SCD1表达抑制脂肪生成。因此,这增加了肝癌细胞对铁凋亡诱导物RSL3的敏感性。此外,AO和RSL3的增强作用,导致显著的肿瘤抑制,在异种移植小鼠模型中得到证实。总之,本研究表明,AO诱导铁凋亡,下调SCD1的表达并增强肝癌细胞对铁凋亡诱导因子RSL3的敏感性。AO和铁凋亡诱导剂的协同使用可能在肝癌细胞中具有有希望的治疗效果。
Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (
SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing
SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of
SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.