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細胞的「鏽蝕」之舞 — 鐵凋亡 Ferroptosis (上篇)

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細胞，也會「生鏽」嗎？

  • 細胞，是生命最基本的單位，它們如何誕生、成長，又如何走向終結？你或許聽過「細胞凋亡」這種程式性的自我毀滅，但如果我告訴你，細胞還有另一種更為劇烈、更具破壞性的死亡方式，它就像金屬生鏽一樣，由「鐵」驅動，最終導致細胞結構崩壞，你是否會感到好奇？
  • 這種獨特的細胞死亡機制，被稱為 Ferroptosis（鐵死亡）。它與我們熟悉的細胞凋亡截然不同，它不走尋常路，而是透過一種危險的化學反應——脂質過氧化來執行死亡任務。近年來，科學家們發現 Ferroptosis 不僅是實驗室裡的新奇現象，更與癌症、神經退化性疾病、器官損傷及發炎反應等眾多疾病息息相關。
  • 今天，我們將深入探索 Ferroptosis 的核心秘密，了解它如何「鏽蝕」細胞，又如何在生命的病理進程中扮演著令人驚訝的角色。
 

細胞內部「生鏽」的秘密：鐵、脂肪與防鏽牆的崩塌

  • 鐵過載：點燃鏽蝕的火花
    • 鐵，是維持生命活動不可或缺的微量元素，它參與氧氣運輸、DNA 合成和能量產生。然而，過猶不及。當細胞內累積過多的亞鐵離子 (Fe2+) 時，它就變成了一把雙刃劍。這些過量的鐵會像失控的催化劑一樣，透過芬頓反應 (Fenton reaction) 大量產生活性氧物種 (ROS)，這正是細胞「生鏽」的引爆點。
    • 細胞內鐵過載的常見途徑包括：細胞膜上的轉鐵蛋白受體 (TFRC) 過度活躍，增加鐵的攝取；或者儲存鐵的蛋白質鐵蛋白 (ferritin) 異常降解，釋放出過量鐵離子，這個過程被稱為鐵蛋白自噬 (ferritinophagy)。
  • 脂質過氧化：細胞膜的腐蝕
    • 一旦 ROS 大量生成，它們會立即攻擊細胞內最脆弱的目標之一：細胞膜上的脂質，特別是含有多不飽和脂肪酸 (PUFAs) 的磷脂。這就像油品長期暴露在空氣中會產生**「油耗味」一樣，活性氧會導致這些脂質發生「氧化生鏽」，即脂質過氧化 (lipid peroxidation)**。
    • 脂質過氧化會破壞細胞膜的完整性，導致粒線體萎縮、膜密度增加和嵴斷裂等形態學變化。最終，細胞膜失去功能，細胞便走向死亡。
  • 防鏽機制失效：為何細胞無法自救？
    • 健康的細胞擁有一套精密的**「防鏽塗層」或「防鏽劑」系統來對抗氧化損傷。其中，系統 Xc- (system Xc-) 負責將半胱胺酸運輸到細胞內，用於合成主要的抗氧化劑穀胱甘肽 (GSH)。而穀胱甘肽過氧化物酶 4 (GPX4)** 則是一種關鍵酶，它利用 GSH 將細胞內的脂質過氧化物還原成無毒的脂質醇，從而保護細胞。
    • 在 Ferroptosis 中，這些關鍵的防禦機制遭到抑制或耗盡。例如，抑制系統 Xc- 的活性（如由 erastin 誘導）會導致 GSH 耗竭，而 GPX4 活性的喪失（如由 RSL3 誘導）則直接導致脂質過氧化物的累積，使得細胞失去抵抗能力，任由「鏽蝕」蔓延。
 

參考文獻

  1. Chen, X., Li, J., Kang, R., Klionsky, D. J., & Tang, D. (2021). Ferroptosis: Machinery and regulation. Autophagy, 17(8), 2054–2081. https://doi.org/10.1080/15548627.2020.1797284
  2. Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D. (2016). Ferroptosis: Process and function. Cell Death & Differentiation, 23(3), 369–379. https://doi.org/10.1038/cdd.2015.158
  3. Gao, M., Monian, F., Pan, Q., Zhang, W., Xiang, J., & Jiang, X. (2018). Ferroptosis is regulated by the TCA cycle and glutaminolysis. Molecular Cell, 72(6), 1017–1028.e3. https://doi.org/10.1016/j.molcel.2018.10.026
  4. Su, X., Wu, P., Sun, Y., Wu, J., Zhang, H., Tang, S., Wang, H., Zhang, Y., Wang, Y., & Tang, Q. (2022). HIF-1α activation mediated roxadustat-induced ferroptosis in chemoresistant GBM cells. Cell Death Discovery, 8(1), Article 273. https://doi.org/10.1038/s41420-022-01073-1
  5. Lee, S., Hwang, N., Seok, B. G., Kim, H., & Lee, E. (2023). Ferroptosis as an emerging target in inflammatory diseases. Progress in Molecular Biology and Translational Science, 172, 1–25. https://doi.org/10.1016/bs.pmbts.2020.02.002
  6. Ma, H., Xu, M., Yu, K., Cao, W., Li, H., Yang, M., Ren, H., Yang, H., Shi, Y., Li, T., Wang, Q., Li, J., Chen, J., Chen, T., & Yu, S. (2023). N-glycosylation of 4F2hc is required for its membrane localization and the interaction with xCT. Cell Death & Differentiation, 30(12), 2567–2581. https://doi.org/10.1038/s41418-023-01188-z
  7. Pan, Z., Van den Bossche, J.-L., Rodriguez-Aznar, E., Janssen, P., Lara, O., Ates, G., Massie, A., De Paep, D. L., Houbracken, I., Mambretti, M., & Rooman, I. (2023). Pancreatic acinar cell fate relies on system xC- to prevent ferroptosis during stress. Cell Death & Disease, 14(10), Article 353. https://doi.org/10.1038/s41419-023-06158-6
  8. Sun, J., Liu, Q., Jiang, Y., Cai, Z., Liu, H., & Zuo, H. (2023). Engineered small extracellular vesicles loaded with miR-654-5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma. Cell Death Discovery, 9(1), Article 362. https://doi.org/10.1038/s41420-023-01660-2
  9. Chuang, Y.-T., Yen, C.-Y., Chien, T.-M., Chang, F.-R., Tsai, Y.-H., Wu, K.-C., Tang, J.-Y., & Chang, H.-W. (2024). Ferroptosis-regulated natural products and miRNAs and their potential targeting to ferroptosis and exosome biogenesis. International Journal of Molecular Sciences, 25(11), Article 6083. https://doi.org/10.3390/ijms25116083
  10. Ren, H., Wang, M., Ma, X., An, L., Guo, Y., & Ma, H. (2024). METTL3 in cancer-associated fibroblasts-derived exosomes promotes the proliferation and metastasis and suppresses ferroptosis in colorectal cancer by eliciting ACSL3 m6A modification. Biology Direct, 13(1), Article 68.
  11. Wang, Y., Zhang, Y., Gao, M., Chen, Z., Lu, J., Li, Y., Di, Y., Zhao, Y., Liu, B., & Tang, R. (2024). Lipocalin-2 promotes CKD vascular calcification by aggravating VSMCs ferroptosis through NCOA4/FTH1-mediated ferritinophagy. Cell Death Discovery, 10(1), Article 114. https://doi.org/10.1038/s41420-024-07260-x
  12. Hu, W., Zhang, Z., Chen, Y., He, H., Wang, W., Yi, X., Li, X., Wang, Y., Zhu, Y., Li, M., Shi, Y., Fang, T., & Chen, X. (2025). The HIF-1α/GPX4 pathway may ameliorate DSS-induced colitis in mice by suppressing ferroptosis in colonic epithelial cells. Cell Death & Disease, 16(1), Article 7883. https://doi.org/10.1038/s41420-025-07883-8
  13. Jiang, H., Wang, X., Zhu, Z., Song, C., Li, D., Yun, Y., Hui, L., Bao, L., O’Connor, D. P., Ma, J., & Xu, G. (2025). DCAF7 recruits USP2 to facilitate hepatocellular carcinoma progression by suppressing clockophagy-induced ferroptosis. Cell Death & Disease, 16(1), Article 340. https://doi.org/10.1038/s41419-025-07873-w
  14. Loo, T. M., Zhou, X., Tanaka, Y., Sugawara, S., Yamauchi, S., Kawasaki, H., Matsuoka, Y., Sugiura, Y., Sakuma, S., Yamanishi, Y., Yotsumoto, S., Dodo, K., Shirasaki, Y., Kamatani, T., & Takahashi, A. (2025). Senescence-associated lysosomal dysfunction impairs cystine deprivation-induced lipid peroxidation and ferroptosis. Nature Communications, 16(1), Article 6617. https://doi.org/10.1038/s41467-025-61894-9
  15. Wang, S., Li, Z., Guo, S., Li, Y., Zhao, Y., Huo, B., Chen, Y., Yi, X., Liu, Y., Zhang, Z., Piao, J., & Jiang, D. S. (2025). ILF3 knockdown sensitizes colorectal cancer cells to ferroptosis by upregulating SLC3A2. Cell Death & Disease, 16(1), Article 7872. https://doi.org/10.1038/s41419-025-07872-x
  16. Yang, M., Wang, T., Shao, J., Ran, X., Xiao, R., Zhao, R., Wu, C., Ji, M., Tian, W., Sun, H., Liu, J., & Zuo, S. (2025). (+)-JQ-1 alleviates cardiac injury in myocardial infarction by inhibiting ferroptosis through the NAMPT/SIRT1 pathway. Cell Death & Disease, 16(1), Article 548. https://doi.org/10.1038/s41419-025-07880-x
  17. Zhang, H., Ma, J., Hou, C., Luo, X., Zhu, S., Peng, Y., Peng, C., Li, P., Meng, H., Xia, Y., Jiang, Z., Modepalli, S., Duttargi, A., Kupfer, G. M., Cai, M., Zhang, H., Ma, J., Li, J., Han, S., & Pei, H. (2025). A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis. Nature Cell Biology, 27(3), 1–12. https://doi.org/10.1038/s41556-025-01722-w
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