2.A.3.8.18
Cystine/glutamate antiporter (Amino acid transport system xCT; Asc1; CD98hc) (Calcium channel blocker resistance protein CCBR1) (Solute carrier family 7 member 11; SLC7A11).  The pathology and development of non-competive diaryl-isoxazole inhibitors have been presented (Newell et al. 2013).  In Lama paco (alpaca), the Slc7a11 porter of 503 aas and 12 TMSs probably functions in melanogenesis and coat color regulation (Tian et al. 2015).  It interacts with mucin-1 (MUC1-C; P15941) which forms a complex with xCT. It also forms a complex with SLC3A2 heavy chain (CD98hc, 4F2hc or MDU1 (TC# 8.A.9.2.2). Together they maintain glutathione levels and redox balance and influence cancer development (Hasegawa et al. 2016). xCT is the receptor for Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8), the causative agent of Kaposi's sarcoma and other lymphoproliferative syndromes often associated with HIV/AIDS (Kaleeba and Berger 2006). Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential, but it seems to have many side effects (Nagane et al. 2018). xCT is a cancer stem cell-related target and can be used to develop preclinical therapeutic approaches, able to hamper tumor growth and dissemination (Ruiu et al. 2019). Residues involved in substrate binding have been proposed based on in silico approaches (Sharma and Anirudh 2019). The tissue distribution of xCT in chickens has been determined (Choi et al. 2020). xCT supports tumor cell growth through glutathione-based oxidative stress resistance, and mutations can enhance its stability (Oda et al. 2020). Signals of pseudo-starvation unveiled that SLC7A11 is key determinant in the control of Treg (T) cell proliferative potential (Procaccini et al. 2021). xCT antiporter function inhibits HIV-1 infection (Rabinowitz et al. 2021). SLC7A11 providess a gateway of metabolic perturbation and ferroptosis vulnerability in cancer (Lee and Roh 2022). CEBPG (CCAAT Enhancer Binding Protein Gamma) suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancer (Zhang et al. 2023). xCT protects cancer cells from oxidative stress and is overexpressed in many cancers. Yan et al. 2023 reported that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H₂O₂, a common oxidative stress inducer, its high overexpression dramatically increases H₂O₂-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H₂O₂ treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). Additionally, high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that xCT expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology (Yan et al. 2023).  By inhibiting the xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated (Yakubov et al. 2023). Butyrate enhances erastin-induced ferroptosis of osteosarcoma cells by regulating the ATF3/SLC7A11 pathway(Nie et al. 2023).  It shows increased activity in ovarian cancer and may be a theraputic target (Fantone et al. 2024; Han et al. 2024). The non-natriuretic-dependent Xc- is composed of two protein subunits, SLC7A11 and SLC3A2, with SLC7A11 being responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is implicated in tumor development through its regulation of redox homeostasis, amino acid metabolism, modulation of immune function, and induction of programmed cell death. Jiang and Sun 2024 summarized the structure and biological functions of SLC7A11. It depends on SLC3A2 (4F2, 4F2HC, CD98, MDU1, NACAE) listed in TCDB under TC# 8.A.9.2.2. Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11 (Han et al. 2024). Targeting sirtuiin-3 (SIRT3) sensitizes glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11 (Li et al. 2024). An inhibitor of SLC7A11 (xCT) has been identified (Yue et al. 2024).  It acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. It forms heterodimers with SLC7 family transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11), a group of amino-acid antiporters (Rossier et al. 1999).  Heterodimers function as amino acids exchangers, the specificity of the substrate depending on the SLC7A subunit. Heterodimers SLC3A2/SLC7A6 or SLC3A2/SLC7A7 mediate the uptake of dibasic amino acids (Bröer et al. 2000.  LAPTM4B (see TC# 2.A.74.1.3) counteracts ferroptosis by suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer (Yan et al. 2024).  STEAP3 (TC# 5.B.6.1.1) affects ovarian cancer progression by regulating ferroptosis through the p53/SLC7A11 pathway (Han et al. 2024).  The E3 ligase TRIM7 suppresses the tumorigenesis of gastric cancer by targeting SLC7A11 (Chen et al. 2024). Sevoflurane-induced neurotoxicity occurs through SLC7A11-associated ferroptosis (Hu et al. 2024). Human USP38 (ubiquitin-specific peptidase 38) exacerbates myocardial injury and malignant ventricular arrhythmias after ischemia/reperfusion by promoting ferroptosis through the P53/SLC7A11 pathway (Gong et al. 2025).