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RanBP2 promotes ferroptosis resistance and compromises therapeutic response by stabilizing SLC7A1 through LRSAM1 SUMOylation and ubiquitination in lung adenocarcinoma
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DOI：10.1038/s41418-026-01837-z.png)
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Abstract
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SUMOylation is characterized as a ubiquitin-like post-translational modification that exhibits mechanistic similarities with ubiquitination. Importantly, it modulates the ubiquitination levels of some target proteins, thereby influencing protein stability. Dysregulation of this modification pathway plays a pivotal role in the pathogenesis and progression of various tumors. While recent studies have demonstrated that protein SUMOylation regulates tumor progression, the specific function and mechanism of Ran-binding protein 2 (RanBP2), an E3 SUMO ligase, remain to be elucidated in lung adenocarcinoma (LUAD). This study demonstrates that RanBP2 exhibits elevated expression in LUAD and correlates with poor prognosis. Functionally, RanBP2 inhibits ferroptosis and enhances the growth of LUAD cells. Mechanistically, RanBP2 augments the SUMOylation of E3 ubiquitin ligase leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1), facilitating its subsequent degradation in the ubiquitin-proteasome pathway, thereby reducing SLC7A11 degradation. The stabilized SLC7A11 protein suppresses ferroptosis and promotes LUAD cell growth. The identified RanBP2 inhibitor, amodiaquine (AQ), in combination with ferroptosis inducer sulfasalazine (SAS), effectively triggered ferroptosis and suppressed LUAD cell growth in vitro and in vivo. This combination enhanced T-cell infiltration and improved anti-PD-1 immunotherapy efficacy. The research identifies a novel RanBP2-LRSAM1-SLC7A11 axis that promotes ferroptosis resistance and LUAD progression. The combination of AQ and SAS represents a promising therapeutic strategy for LUAD.
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