The Role of SLC7A11 in Tumor Progression and the Regulation Mechanisms Involved in Ferroptosis.

Abstract

SLC7A11 (xCT) is a key subunit of the cysteine/glutamate transporter (system xc ^-), which is crucial for maintaining cellular redox homeostasis (especially glutathione synthesis) and regulating Ferroptosis. It is highly expressed in various malignant tumors and is a key factor leading to treatment resistance, making it an important anti-cancer target. This review systematically summarizes the complex multi-level regulatory network of SLC7A11: at the transcriptional level, key factors form precise regulatory hubs: the KEAP1/NRF2 pathway directly activates SLC7A11 transcription, endowing cancer cells with antioxidant and anti ferroptotic abilities; P53 acts as a core inhibitory factor, and its activity state (activated by STEAP3 iron overload or regulated by Gankyrin/DM2 degradation) directly determines the intensity of inhibition of SLC7A11; ATF4 integrates endoplasmic reticulum stress, oxidative damage, and epigenetic signals (such as SIRT3/KDM3B/KDM4A), and bidirectionally regulates SLC7A11 transcription. Epigenetic regulation involves RNA m6A modification (ALKBH5/FTO reduces stability, METTL3/IGF2BP3 enhances stability) and histone modification (BAP1/PRC1 inhibits through H2Aub). After translation, the stability of SLC7A11 protein is strictly regulated by ubiquitination (SOCS2/HECTD3 promotes degradation, OTUB1/TCF12 inhibits degradation) and palmitoylation (ZDHHC8/DUXAP8 antagonizes degradation). Of particular importance is that non coding RNAs indirectly release their inhibition of SLC7A11 mRNA by acting as "molecular sponges" to adsorb specific miRNAs, profoundly affecting tumor progression and resistance to ferroptosis. This study reveals how cancer cells abnormally upregulate SLC7A11 by hijacking multi-level mechanisms, gaining strong antioxidant/anti ferroptotic abilities, which are the core basis for their survival, proliferation, and resistance to treatment. This study also identified SLC7A11 as a convergence point for multiple key pathways, making it an ideal hub target for intervening in cancer and overcoming drug resistance.