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 Fe 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.