Targeting ZNRF2-mediated SLC3A2 plasma membrane translocation enhances ferroptosis in lung adenocarcinoma

Zinc And Ring Finger 2 (ZNRF2), an important protein related to E3 ligases activity, known for its support of cell viability of lung adenocarcinoma (LUAD), remains a functional mystery as its mechanism of action remains largely unknown. SLC3A2, a cell surface transmembrane protein, which regulates intracellular calcium levels and transports L-type amino acids, also has unclear mechanisms, particularly involving its expression and localization. In the present study, we addressed the role of ZNRF2-mediated SLC3A2 plasma membrane translocation, which influences ferroptosis in LUAD. We found that ZNRF2 exhibited ubiquitous expression in LUAD, and supported cell viability via ferroptosis inhibition. Mechanistically, ZNRF2 impacted SLC3A2 membrane localization and ferroptosis by fine-tuning K147-mediated ubiquitination. We subsequently synthesized Peptide K147 to block transportation of the SLC3A2 protein to the plasma membrane, which consequently attenuated the inhibitory effect of ZNRF2 on ferroptosis, thereby preventing tumor cell proliferation both in vitro and in vivo. Finally, we revealed that the ZNRF2- mediated SLC3A2 plasma membrane transport enhanced LUAD chemoresistance, whereas, Peptide K147 facilitated LUAD chemosensitization. Our results demonstrated that ZNRF2-mediated SLC3A2 plasma membrane translocation potentially contributes to the malignant progression and therapeutic resistance in LUAD. This knowledge is beneficial to the future design of advanced cancer therapy.