表1 鐵死亡的誘導(dǎo)劑與抑制劑[1~4]

1,、自噬通過鐵蛋白降解調(diào)控鐵死亡

鐵死亡最近被描述為一種自噬性細胞死亡過程，自噬通過調(diào)節(jié)細胞內(nèi)鐵穩(wěn)態(tài)和活性氧產(chǎn)生,，在誘導(dǎo)鐵死亡發(fā)生過程中發(fā)揮核心作用[5],。

2、鐵死亡調(diào)控因子被轉(zhuǎn)運至溶酶體中,，并通過自噬過程執(zhí)行其功能

Keap-NRF2信號通路可能是鐵死亡與自噬之間的重要聯(lián)系[6-7],。RNA結(jié)合蛋白ELAVL1/HuR在調(diào)節(jié)肝纖維化鐵死亡中起到重要作用[8]，鐵死亡誘導(dǎo)劑通過抑制泛素蛋白酶體途徑提高ELAVL1蛋白水平,，同時下調(diào)ELAVL1蛋白能促進自噬體產(chǎn)生,。Beclin-1通過與SLC7A11直接相互作用，誘導(dǎo)脂質(zhì)過氧化并通過阻斷System Xc-的活性來促進鐵死亡[9],。p53激活抑制mTOR活性,，隨后促進自噬發(fā)生[10]；最近還發(fā)現(xiàn)核p53以轉(zhuǎn)錄依賴的方式刺激鐵死亡,，通過抑制編碼System Xc-的基因SLC7A11的表達,，抑制胱氨酸攝取和細胞對鐵死亡的敏感性。

Fig. 4[4] 鐵死亡與自噬的交互作用示意圖  A：鐵死亡與自噬交互作用的總體機制 B：p53在鐵死亡與自噬交互作用中的作用 C：Beclin-1在鐵死亡與自噬交互作用中的作用 D：在鐵死亡與自噬交互作用當(dāng)中涉及到的其他關(guān)鍵分子和通路

3、癌癥耐藥中細胞自噬與鐵死亡的相互關(guān)系

Fig. 5[4]  自噬與鐵死亡在耐藥中微調(diào)轉(zhuǎn)換

參考文獻

[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.