Slc3a2, also known as 4F2hc or CD98, is a multifunctional glycoprotein. It acts as a disulfide-linked adaptor to SLC7A5 and SLC7A11 exchangers, importing essential amino acids and cystine while exporting Gln and Glu respectively. It is involved in processes like oxidative metabolism, proteostasis, and regulation of amino-acid-sensing and mTORC1 activation. It participates in pathways related to cell growth, metabolism, and stress mitigation [5,4].

In lung cancer, knockdown of Slc3a2 in lung adenocarcinoma cells impaired M2 polarization of macrophages, suggesting it promotes tumor-associated macrophage polarization through metabolic reprogramming, likely via arachidonic acid [1]. In osteoarthritis, Slc3a2 was down-regulated in OA cartilage compared to normal cartilage, and in vitro experiments validated that it inhibited ferroptosis and suppressed cartilage degeneration [3]. In laryngeal carcinoma, Slc3a2 deficiency inhibited cell proliferation, induced ferroptosis, and suppressed tumorigenesis in nude mice, indicating it negatively regulates ferroptosis through the mTOR pathway [8]. In breast cancer, short-term acidosis restrained the protein stability of Slc3a2 by promoting its ubiquitination, inducing ferroptosis and M1 macrophage polarization [7]. In alcohol-associated liver cancer, SLC3A2, as an indirect target gene of ALDH2, exacerbates the disease via the sphingolipid biosynthesis pathway [6]. In ApoE-/-mice, metabolite Neu5Ac triggers SLC3A2 degradation, promoting vascular endothelial ferroptosis and aggravating atherosclerosis progression [2]. In neuroblastoma, Anaplastic Lymphoma Kinase signaling stabilizes SLC3A2 expression via MARCH11 to promote cell growth, and combined inhibition of ALK and polyamine transport (related to SLC3A2) shows synergistic inhibition of cell growth [9].

In conclusion, Slc3a2 plays diverse and crucial roles in multiple biological processes and disease conditions. Through gene-knockout or knockdown models in various tissues, its functions in tumor-associated macrophage polarization, ferroptosis regulation in different cancers, cartilage degeneration in osteoarthritis, and atherosclerosis progression have been revealed. These findings contribute to understanding disease mechanisms and potentially developing targeted therapies for lung cancer, osteoarthritis, laryngeal carcinoma, breast cancer, alcohol-associated liver cancer, atherosclerosis, and neuroblastoma.

References:

1. Li, Zhuan, Chen, Songming, He, Xiang, Sun, Lunquan, Weng, Liang. 2023. SLC3A2 promotes tumor-associated macrophage polarization through metabolic reprogramming in lung cancer. In Cancer science, 114, 2306-2317. doi:10.1111/cas.15760. https://pubmed.ncbi.nlm.nih.gov/36793241/

2. Xiang, Peng, Chen, Qingqiu, Chen, Le, Yu, Chao, Ma, Limei. 2023. Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice. In Theranostics, 13, 4993-5016. doi:10.7150/thno.87968. https://pubmed.ncbi.nlm.nih.gov/37771765/

3. Liu, Hailong, Deng, Zengfa, Yu, Baoxi, Zeng, Anyu, Fu, Ming. 2022. Identification of SLC3A2 as a Potential Therapeutic Target of Osteoarthritis Involved in Ferroptosis by Integrating Bioinformatics, Clinical Factors and Experiments. In Cells, 11, . doi:10.3390/cells11213430. https://pubmed.ncbi.nlm.nih.gov/36359826/

4. Nachef, Marianna, Ali, Alaa Kassim, Almutairi, Saeedah Musaed, Lee, Seung-Hwan. 2021. Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment. In Frontiers in immunology, 12, 624324. doi:10.3389/fimmu.2021.624324. https://pubmed.ncbi.nlm.nih.gov/33953707/

5. Zhang, Cunjie, Shafaq-Zadah, Massiullah, Pawling, Judy, Johannes, Ludger, Dennis, James W. 2023. SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation. In The Journal of biological chemistry, 299, 105416. doi:10.1016/j.jbc.2023.105416. https://pubmed.ncbi.nlm.nih.gov/37918808/

6. Xia, Pu, Liu, Da-Hua, Wang, Dan, Wen, Gui-Min, Zhao, Zhen-Ying. 2023. SLC3A2, as an indirect target gene of ALDH2, exacerbates alcohol-associated liver cancer via the sphingolipid biosynthesis pathway. In Free radical biology & medicine, 206, 125-133. doi:10.1016/j.freeradbiomed.2023.07.002. https://pubmed.ncbi.nlm.nih.gov/37406742/

7. Xiong, Hanchu, Zhai, Yanan, Meng, Yimei, Wang, Geyi, Yang, Liu. 2024. Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization. In Cancer letters, 587, 216732. doi:10.1016/j.canlet.2024.216732. https://pubmed.ncbi.nlm.nih.gov/38360142/

8. Wu, Fangxing, Xiong, Gaoyun, Chen, Zejun, Liu, Qianqian, Bai, Yundan. 2022. SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway. In Hereditas, 159, 6. doi:10.1186/s41065-022-00225-0. https://pubmed.ncbi.nlm.nih.gov/35057861/

9. Lai, Wei-Yun, Chuang, Tzu-Po, Borenäs, Marcus, Hallberg, Bengt, Palmer, Ruth H. 2024. Anaplastic Lymphoma Kinase signaling stabilizes SLC3A2 expression via MARCH11 to promote neuroblastoma cell growth. In Cell death and differentiation, 31, 910-923. doi:10.1038/s41418-024-01319-0. https://pubmed.ncbi.nlm.nih.gov/38858548/