Tnfaip1, short for tumor necrosis factor α-induced protein 1, was first identified in human umbilical vein endothelial cells and can be induced by TNFα. It plays a role in multiple cellular biological functions, such as regulating DNA replication, repair, and the cell cycle through binding to target proteins [5]. It is also involved in various pathways like the LEENE/FoxO1/ABCA1 pathway, Akt/CREB pathway, p38/JNK pathway, and PI3K/Akt/Nrf2 pathway, and is associated with diseases including atherosclerosis, neurological disorders, and renal cell carcinoma [3,4,6,8]. Zebrafish and mouse models have been valuable for studying its functions [2,5].

In mice, neuron-specific knockdown of Tnfaip1 alleviates postoperative cognitive dysfunction by enhancing mitophagy and reducing pyroptosis, achieved by inhibiting the K48-linked polyubiquitination of SNAP25 by Tnfaip1 [1]. In zebrafish, knockout of tnfaip1 leads to developmental delays, microcephaly, microphthalmia, and altered expression of neuronal marker genes and embryonic development-related genes [2]. In THP-1 macrophage-derived foam cells and apoE-/-mice, knockdown of Tnfaip1 suppresses lipid accumulation and attenuates atherosclerotic lesion area via the LEENE/FoxO1/ABCA1 pathway [3]. In N2a cells, knockdown of Tnfaip1 prevents formaldehyde-induced inhibition of the Akt/CREB pathway, reducing cell apoptosis [4]. In renal cell carcinoma cells, HECTD2 up-regulates TNFAIP1 to promote an inflammatory response through the p38/JNK pathway [6]. In PC12 cells, knocking down TNFAIP1 alleviates oxygen-glucose deprivation and reperfusion-induced neuronal damage by suppressing Nrf2-mediated ferroptosis [7]. In LPS-induced pneumonia mice, silencing TNFAIP1 alleviates the inflammatory response, ROS production, and cellular apoptosis via the PI3K/Akt/Nrf2 pathway [8]. In SH-SY5Y cells, TNFAIP1 promotes apoptosis by binding to RhoB, and this is relevant to Alzheimer's disease pathogenesis [9]. In hepatocellular carcinoma cells, down-regulation of TNFAIP1 induces the expression of pro-inflammatory cytokines via the p38/JNK MAPK pathway by blocking RhoB degradation [10].

In conclusion, Tnfaip1 is involved in multiple biological processes such as development, lipid metabolism, inflammation, and apoptosis, and is associated with various diseases. Studies using gene knockout or knockdown models in mice, zebrafish, and cell lines have revealed its functions in these processes and diseases, providing potential therapeutic targets for conditions like postoperative cognitive dysfunction, atherosclerosis, neurological disorders, renal cell carcinoma, and pneumonia.

References:

1. Wang, Wei, Gao, Wenwei, Gong, Ping, Zhang, Lei, Zhao, Bo. 2023. Neuronal-specific TNFAIP1 ablation attenuates postoperative cognitive dysfunction via targeting SNAP25 for K48-linked ubiquitination. In Cell communication and signaling : CCS, 21, 356. doi:10.1186/s12964-023-01390-z. https://pubmed.ncbi.nlm.nih.gov/38102610/

2. Huang, Shulan, Zhang, Hongning, Chen, Wen, Xiang, Shuanglin, Hu, Xiang. 2023. Nuclease technology-Mediated Knockout of tnfaip1 in Zebrafish Plays a Role in Early Development. In Genes, 14, . doi:10.3390/genes14051005. https://pubmed.ncbi.nlm.nih.gov/37239365/

3. Xu, Can, Meng, Jun, Yu, Xiao-Hua, Yin, Shan-Hui, Wang, Gang. 2024. TNFAIP1 promotes macrophage lipid accumulation and accelerates the development of atherosclerosis through the LEENE/FoxO1/ABCA1 pathway. In Journal of physiology and biochemistry, 80, 523-539. doi:10.1007/s13105-024-01018-x. https://pubmed.ncbi.nlm.nih.gov/38878215/

4. Yi, Junzhi, Zhu, Min, Qiu, Feng, Wei, Chenxi, Xiang, Shuanglin. 2020. TNFAIP1 Mediates Formaldehyde-Induced Neurotoxicity by Inhibiting the Akt/CREB Pathway in N2a Cells. In Neurotoxicity research, 38, 184-198. doi:10.1007/s12640-020-00199-9. https://pubmed.ncbi.nlm.nih.gov/32335808/

5. Huang, Shulan, Zhang, Hongning, Chen, Wen, Hu, Xiang, Xiang, Shuanglin. 2023. Screening of Tnfaip1-Interacting Proteins in Zebrafish Embryonic cDNA Libraries Using a Yeast Two-Hybrid System. In Current issues in molecular biology, 45, 8215-8226. doi:10.3390/cimb45100518. https://pubmed.ncbi.nlm.nih.gov/37886961/

6. Lv, Dong, Chen, Yongbo, Tang, Liangyou, Jian, Nenghong, Shen, Taimin. . HECTD2/TNFAIP1 Axis Regulating the p38/JNK Pathway to Promote an Inflammatory Response in Renal Cell Carcinoma Cells. In In vivo (Athens, Greece), 38, 1094-1103. doi:10.21873/invivo.13543. https://pubmed.ncbi.nlm.nih.gov/38688591/

7. Xiong, Lie, Zhang, Jingruo, Shi, Hanqiang, Zhu, Ping, Luo, Kaitao. 2022. Downregulation of TNFAIP1 alleviates OGD/R‑induced neuronal damage by suppressing Nrf2/GPX4‑mediated ferroptosis. In Experimental and therapeutic medicine, 25, 25. doi:10.3892/etm.2022.11724. https://pubmed.ncbi.nlm.nih.gov/36561622/

8. Chen, Jing, Zhao, Mengtian, Fang, Wei, Du, Chaojun. 2023. Knocking down TNFAIP1 alleviates inflammation and oxidative stress in pediatric pneumonia through PI3K/Akt/Nrf2 pathway. In Allergologia et immunopathologia, 51, 94-100. doi:10.15586/aei.v51i4.884. https://pubmed.ncbi.nlm.nih.gov/37422785/

9. Xiao, Ye, Li, Yadan, Zhang, Huihui, Xiang, Shuanglin, Liu, Ning. 2020. TNFAIP1 Is Upregulated in APP/PS1 Mice and Promotes Apoptosis in SH-SY5Y Cells by Binding to RhoB. In Journal of molecular neuroscience : MN, 71, 1221-1233. doi:10.1007/s12031-020-01748-9. https://pubmed.ncbi.nlm.nih.gov/33159672/

10. Liu, Yue, Zhang, Wenjuan, Wang, Shiwen, Zhao, Hu, Zhang, Yanmei. 2021. Cullin3-TNFAIP1 E3 Ligase Controls Inflammatory Response in Hepatocellular Carcinoma Cells via Ubiquitination of RhoB. In Frontiers in cell and developmental biology, 9, 617134. doi:10.3389/fcell.2021.617134. https://pubmed.ncbi.nlm.nih.gov/33553178/