Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.

Abstract

OBJECTIVE: Overcoming resistance to Osimertinib remains a major clinical challenge in lung adenocarcinoma (LUAD). The molecular mechanisms driving this resistance are still not fully understood. METHODS: Integrated bioinformatics analysis and functional assays were performed to investigate the role of SLC25A39 in LUAD progression and drug resistance. Mechanistic studies were conducted using co-immunoprecipitation and rescue experiments. Osimertinib-resistant cell models and xenograft assays were used to evaluate therapeutic responses. RESULTS: SLC25A39 was significantly upregulated in LUAD and correlated with unfavorable patient outcomes. Functional studies showed that SLC25A39 depletion suppressed malignant phenotypes and enhanced ferroptosis, whereas its overexpression produced the opposite effects. Mechanistically, SLC25A39 was found to interact with NRF2 and was associated with increased NRF2 stability and transcriptional activity, leading to enhanced glutathione synthesis and attenuation of lipid peroxidation. Importantly, silencing SLC25A39 sensitized LUAD cells to Osimertinib. Consistent with this, pharmacological induction of ferroptosis using RSL3 markedly enhanced the antitumor effects of Osimertinib in both parental and resistant models, resulting in reduced tumor growth in vitro and in vivo, particularly in SLC25A39-high contexts. CONCLUSION: SLC25A39 promotes LUAD progression and Osimertinib resistance by suppressing ferroptosis via NRF2. Targeting ferroptosis may represent a promising strategy to overcome Osimertinib resistance.

Key Findings

• SLC25A39 is upregulated in lung adenocarcinoma and correlates with poor patient outcomes.
• SLC25A39 interacts with NRF2, increasing its stability and transcriptional activity, which enhances glutathione synthesis and reduces lipid peroxidation, thereby suppressing ferroptosis.
• Silencing SLC25A39 sensitizes lung adenocarcinoma cells to Osimertinib, and pharmacological induction of ferroptosis enhances Osimertinib's antitumor effects in both parental and resistant models.

Clinical Significance

Citation

Fu Kai, Zeng Zhilin, Wang Wenfenget al.. Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma. Cellular and molecular life sciences : CMLS. 2026-Jul-06.