Slc3a2, also known as 4F2hc and CD98, is a disulfide-linked adaptor to the SLC7A5 and SLC7A11 exchangers. It is involved in the import of essential amino acids and cystine, and the export of Gln and Glu. It plays a role in oxidative metabolism-related proteostasis and is associated with pathways such as mTORC1 signaling. It is crucial for normal cellular growth and metabolism [4,5].

In lung cancer, knockdown of Slc3a2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in a coculture system, suggesting it promotes tumor-associated macrophage polarization through metabolic reprogramming [1]. In ApoE-/-mice, metabolite Neu5Ac triggered Slc3a2 degradation, promoting vascular endothelial ferroptosis and aggravating atherosclerosis progression [2]. 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 is highly expressed, and its deficiency inhibited cell proliferation, induced ferroptosis, and suppressed tumorigenesis in nude mice via the mTOR pathway [6]. In head and neck squamous cell carcinomas, SLC3A2-deficient cells showed higher radiosensitivity and increased autophagy levels [7].

In summary, Slc3a2 plays important roles in multiple biological processes and disease conditions. Its deficiency in various KO models reveals its functions in tumor-associated macrophage polarization, endothelial ferroptosis, cartilage degeneration, tumor cell proliferation, and radiosensitivity, highlighting its potential as a therapeutic target in cancer, atherosclerosis, and osteoarthritis.