AUTHOR=Cai Wenhan , Liu Yiming , Zhao Kai , Zhu Zirui , Jin Jiamei , Wen Jiaxin , Xue Zhiqiang 

TITLE=SLC16A3 drives lung adenocarcinoma progression and gefitinib resistance through coordinated regulation of ferroptosis and lactate metabolism

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1699540

DOI=10.3389/fimmu.2025.1699540

ISSN=1664-3224

ABSTRACT=BackgroundFerroptosis is an iron-dependent form of regulated cell death that plays a critical role in tumor suppression and therapeutic response. However, the metabolic mechanisms that drive ferroptosis resistance in lung adenocarcinoma (LUAD), particularly in the context of EGFR-TKI tolerance, remain unclear.MethodsWe integrated transcriptomic and clinical data from TCGA LUAD cohort and performed survival and enrichment analyses. Functional assays, including proliferation, invasion, ferroptosis indicators, and in vivo xenograft models, were used to evaluate the role of SLC16A3. Lactate rescue, transcription factor prediction (JASPAR), mIHC, and luciferase reporter assays were used to dissect regulatory mechanisms. Pharmacological inhibition of SLC16A3 was used to assess its therapeutic potential.ResultsSLC16A3 expression was elevated in LUAD and was correlated with poor prognosis. SLC16A3 knockdown suppressed tumor cell growth and enhanced ferroptosis, as indicated by increased lipid peroxidation, iron accumulation, and mitochondrial depolarization. Lactate supplementation partially reversed ferroptosis induction. Mechanistically, SLC16A3 was transcriptionally activated by HIF1A, and the HIF1A-SLC16A3 axis conferred ferroptosis resistance and gefitinib tolerance. SLC16A3 inhibition restored ferroptotic sensitivity and enhanced EGFR-TKI efficacy in xenograft models in vivo.ConclusionOur findings reveal that the HIF1A-SLC16A3-lactate axis orchestrates ferroptosis suppression and therapeutic resistance in LUAD. Targeting SLC16A3 represents a promising metabolic strategy for overcoming EGFR-TKI resistance by reactivating ferroptosis.