Identification and molecular mechanism study of a novel small molecule inhibitor targeting solute carrier family 7 member 11 for the treatment of hepatocellular carcinoma†

Ferroptosis plays an extremely significant role in the development of hepatocellular carcinoma (HCC), and targeting tumor cells to induce ferroptosis has emerged as a new approach for the treatment of cancer. Solute carrier family 7 member 11 (SLC7A11) is regarded as a key regulatory factor in ferroptosis, and inhibition of SLC7A11 could suppress tumor cell growth by inducing ferroptosis. In this research, we combined virtual screening with activity evaluation to identify SLC7A11 inhibitor 1b and further explored its underlying molecular mechanism for HCC treatment through network pharmacology. Experimental results demonstrated that compound 1b could effectively inhibit the proliferation of HepG2 cells. In addition, it exhibited a superior effect in inducing ferroptosis compared with the ferroptosis inducer erastin. Moreover, cellular thermal shift assay (CETSA) validated that compound 1b could bind to SLC7A11. Meanwhile, PHE336, ILE52, GLN191, THR56, ILE192 and PHE254 were identified as the key residues. Dynamic cross-correlation matrix (DCCM) analysis and principal component analysis (PCA) demonstrated that when compound 1b bound to SLC7A11, it could change the flexibility of the protein and the trend of residue movements. Analysis of the results revealed that the therapeutic effect of 1b on HCC might occur through targeting SLC7A11,thereby affecting signaling pathways such as the estrogen signaling pathway and VEGF signaling pathway. In conclusion, this study provides insights for the development of SLC7A11 inhibitors.