BECN1 activator peptide Tat-beclin 1 promotes ferroptosis via the BECN1-SLC7A11 axis to inhibit NSCLC progression

Non-small-cell lung cancer (NSCLC) is associated with high mortality. Beclin 1 (BECN1), an autophagy regulator, and ferroptosis, a lipid peroxidation-driven cell death, are both linked to cancer suppression. This study examines whether the BECN1 activator peptide, Tat-Beclin 1, induces ferroptosis in NSCLC by targeting solute carrier family 7 member 11 (SLC7A11). BECN1 expression in NSCLC tissues and cells was assessed using RT-qPCR, western blot, and immunohistochemistry. Functional assays included CCK-8 for cell viability, C11-BODIPY for lipid peroxidation, glutathione (GSH) and glutamate release, glutathione peroxidase 4 (GPX4) activity, and western blotting for iron metabolism markers (ferritin heavy chain 1 [FTH1], ferritin light chain [FTL], and transferrin receptor [TFRC]). BECN1-SLC7A11 interactions were examined using co-immunoprecipitation and immunofluorescence. BECN1 was knocked down using small hairpin RNA (shRNA), and its effects on ferroptosis were evaluated. System Xc⁻ activity was assessed in control, Tat-beclin 1, Tat-beclin 1 + shRNA-NC, and Tat-Beclin 1 + shRNA-BECN1 groups. Tumor suppression by Tat-beclin 1, erastin, and their combination was assessed in vivo using xenograft models. BECN1 expression was downregulated in NSCLC tissues and cells. Treating NSCLC cells with Tat-beclin 1 upregulated BECN1 expression and promoted ferroptosis, as evidenced by increased lipid peroxidation and malondialdehyde content, reduced GSH and GPX4 activity, and decreased cell viability, without affecting Fe²⁺ levels or the expression of iron metabolism-related proteins (FTH1, FTL, and TFRC). Knocking down BECN1 attenuated these effects, confirming its central role. BECN1 interacted with SLC7A11 to inhibit system Xc⁻, an effect abolished by knocking down BECN1. Co-treatment with Tat-beclin 1 and erastin enhanced BECN1-SLC7A11 complex formation, more strongly inhibited system Xc⁻, enhanced lipid peroxidation, inhibited the Nrf2-Keap1 signaling pathway and significantly suppressed tumor growth in vivo. Tat-beclin 1 promotes ferroptosis and tumor suppression in NSCLC by activating BECN1 and inhibiting SLC7A11-mediated system Xc⁻ activity.