Tfrc, also known as transferrin receptor 1, is a key protein involved in iron uptake. It binds to transferrin, which transports iron in the blood, enabling cells to take up iron. This process is crucial for maintaining iron homeostasis, a fundamental aspect of many cellular functions such as DNA synthesis, energy metabolism, and antioxidant defense. Ferroptosis, an iron-dependent form of programmed cell death, is one of the associated pathways [1-10].

In multiple disease conditions, Tfrc has been shown to play a significant role in ferroptosis. In CVB3 infection, upregulation of Tfrc promotes ferroptosis, and downregulation of Tfrc attenuates it. CVB3 induces the nuclear translocation of Tfrc, and the transcription factor Sp1 binds to the Tfrc promoter to upregulate its transcription [1]. In temporomandibular joint osteoarthritis (TMJOA), inflammation triggers chondrocyte ferroptosis via the HIF-1α/Tfrc axis. Upregulation of Tfrc promotes Fe2+ entry into chondrocytes, leading to lipid peroxidation and ferroptosis [2]. In older livers, FTO deficiency exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating Tfrc, among other factors [3]. In liver fibrosis, exosomal miR-222 from hepatitis B virus-infected hepatocytes promotes fibrosis by suppressing Tfrc-induced ferroptosis [4]. In doxorubicin-induced cardiomyocyte injury, METTL14 promotes ferroptosis by regulating the KCNQ1OT1-miR-7-5p-Tfrc axis [5]. Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via Tfrc-dependent ferroptosis as it facilitates the recycling of Tfrc, disrupting iron homeostasis [6]. Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of Tfrc-mediated ferroptosis [7]. In hepatocellular carcinoma cells, O-GlcNAcylation of Tfrc regulates its stability and the sensitivity to ferroptosis [8]. In colorectal cancer, knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated Tfrc degradation [9]. In sepsis-associated encephalopathy, exosome-derived lncRNA NEAT1 exacerbates the condition by promoting ferroptosis through regulating the miR-9-5p/Tfrc axis [10].

In conclusion, Tfrc is essential for cellular iron uptake and maintaining iron homeostasis. Through studies in various disease models, it has been shown that Tfrc-mediated ferroptosis is involved in multiple disease processes, including viral infections, osteoarthritis, liver injury, fibrosis, and cardiomyopathy. These findings highlight the potential of targeting Tfrc-related pathways for therapeutic intervention in these diseases.

References:

1. Yi, Lu, Hu, Yanan, Wu, Zhixiang, Zuoyuan, Bojiao, Yang, Zuocheng. 2022. TFRC upregulation promotes ferroptosis in CVB3 infection via nucleus recruitment of Sp1. In Cell death & disease, 13, 592. doi:10.1038/s41419-022-05027-w. https://pubmed.ncbi.nlm.nih.gov/35821227/

2. Chen, B Y, Pathak, J L, Lin, H Y, Diekwisch, T G H, Liu, C. 2024. Inflammation Triggers Chondrocyte Ferroptosis in TMJOA via HIF-1α/TFRC. In Journal of dental research, 103, 712-722. doi:10.1177/00220345241242389. https://pubmed.ncbi.nlm.nih.gov/38766865/

3. Li, Rong, Yan, Xijing, Xiao, Cuicui, Zheng, Jun, Yang, Yang. 2024. FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. In Nature communications, 15, 4760. doi:10.1038/s41467-024-49202-3. https://pubmed.ncbi.nlm.nih.gov/38834654/

4. Zhang, Qidi, Qu, Ying, Zhang, Qingqing, Lu, Lungen, Cai, Xiaobo. 2022. Exosomes derived from hepatitis B virus-infected hepatocytes promote liver fibrosis via miR-222/TFRC axis. In Cell biology and toxicology, 39, 467-481. doi:10.1007/s10565-021-09684-z. https://pubmed.ncbi.nlm.nih.gov/34978008/

5. Zhuang, Shaowei, Ma, Yan, Zeng, Yuxiao, Zhang, Jiehan, Jiang, Shengyang. 2021. METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis. In Cell biology and toxicology, 39, 1015-1035. doi:10.1007/s10565-021-09660-7. https://pubmed.ncbi.nlm.nih.gov/34648132/

6. Yu, Wenjing, Hu, Yuehuai, Liu, Zhiping, Liu, Peiqing, Lu, Jing. 2023. Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis. In Acta pharmaceutica Sinica. B, 13, 4875-4892. doi:10.1016/j.apsb.2023.08.016. https://pubmed.ncbi.nlm.nih.gov/38045054/

7. Wu, Lin, Du, Yuxin, Wang, Litao, Zhang, Yingmei, Ren, Jun. 2024. Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis. In Redox biology, 72, 103157. doi:10.1016/j.redox.2024.103157. https://pubmed.ncbi.nlm.nih.gov/38631119/

8. Zhou, Xunyu, Wang, Yida, Li, Xiaoyu, Wu, Chuanfang, Bao, Jinku. 2024. O-GlcNAcylation regulates the stability of transferrin receptor (TFRC) to control the ferroptosis in hepatocellular carcinoma cells. In Redox biology, 73, 103182. doi:10.1016/j.redox.2024.103182. https://pubmed.ncbi.nlm.nih.gov/38744192/

9. Wang, Xinyuan, Zhou, Yujie, Ning, Lijun, Chen, Huimin, Li, Xiaobo. 2023. Knockdown of ANXA10 induces ferroptosis by inhibiting autophagy-mediated TFRC degradation in colorectal cancer. In Cell death & disease, 14, 588. doi:10.1038/s41419-023-06114-2. https://pubmed.ncbi.nlm.nih.gov/37666806/

10. Wei, Xue-Biao, Jiang, Wen-Qiang, Zeng, Ju-Hao, Li, Yi-Chen, Chen, Sheng-Long. 2022. Exosome-Derived lncRNA NEAT1 Exacerbates Sepsis-Associated Encephalopathy by Promoting Ferroptosis Through Regulating miR-9-5p/TFRC and GOT1 Axis. In Molecular neurobiology, 59, 1954-1969. doi:10.1007/s12035-022-02738-1. https://pubmed.ncbi.nlm.nih.gov/35038133/