表1 铁死亡的诱导剂与抑制剂[1~4]

1、自噬通过铁蛋白降解调控铁死亡

铁死亡最近被描述为一种自噬性细胞死亡过程，自噬通过调节细胞内铁稳态和活性氧产生，在诱导铁死亡发生过程中发挥核心作用[5]。

2、铁死亡调控因子被转运至溶酶体中，并通过自噬过程执行其功能

Keap-NRF2信号通路可能是铁死亡与自噬之间的重要联系[6-7]。RNA结合蛋白ELAVL1/HuR在调节肝纤维化铁死亡中起到重要作用[8]，铁死亡诱导剂通过抑制泛素蛋白酶体途径提高ELAVL1蛋白水平，同时下调ELAVL1蛋白能促进自噬体产生。Beclin-1通过与SLC7A11直接相互作用，诱导脂质过氧化并通过阻断System Xc-的活性来促进铁死亡[9]。p53激活抑制mTOR活性，随后促进自噬发生[10]；最近还发现核p53以转录依赖的方式刺激铁死亡，通过抑制编码System Xc-的基因SLC7A11的表达，抑制胱氨酸摄取和细胞对铁死亡的敏感性。

Fig. 4[4] 铁死亡与自噬的交互作用示意图  A：铁死亡与自噬交互作用的总体机制 B：p53在铁死亡与自噬交互作用中的作用 C：Beclin-1在铁死亡与自噬交互作用中的作用 D：在铁死亡与自噬交互作用当中涉及到的其他关键分子和通路

3、癌症耐药中细胞自噬与铁死亡的相互关系

Fig. 5[4]  自噬与铁死亡在耐药中微调转换

参考文献

[1]Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future[J]. Cell Death & Disease, 2020, 11:88, https://doi.org/10.1038/s41419-020-2298-2.

[2]Cao JY, Dixon SJ. Mechanisms of ferroptosis[J]. Cell. Mol. Life Sci. 2016, 73:2195–2209.

[3]Bebber CM, Müller F, Clemente LP, et al. Ferroptosis in Cancer Cell Biology[J]. Cancers ,2020, 12, 164; doi:10.3390/cancers12010164.

[4]Zhou YL, Shen Y, Chen C,et al. The crosstalk between autophagy and ferroptosis: what can we learn to target drug resistance in cancer?[J]. Cancer Biol Med, 2019, doi: 10.20892/j.issn.2095-3941.2019.0158.

[5]Gao MH, Monian P, Pan QH, Zhang W, Xiang J, Jiang XJ. Ferroptosis is an autophagic cell death process[J]. Cell Res, 2016, 26: 1021-32.

[6]Sun XF, Ou ZH, Chen RC, Niu XH, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016; 63: 173-84.

[7] Inoue H, Kobayashi KI, Ndong M, Yamamoto Y, Katsumata SI, Suzuki K, et al. Activation of Nrf2/Keap1 signaling and autophagy induction against oxidative stress in heart in iron deficiency. Biosci Biotechnol Biochem. 2015; 79: 1366-8.

[8]Zhang ZL, Yao Z, Wang L, Ding H, Shao JJ, Chen AP, et al. Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. 2018; 14: 2083-103.

[9] Kang R, Zhu S, Zeh HJ, Klionsky DJ, Tang DL. BECN1 is a new driver of ferroptosis. Autophagy. 2018; 14: 2173-5.