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

## TL;DR

This study shows that SLC16A3 promotes lung cancer growth and drug resistance by controlling cell death and lactate metabolism.

## Contribution

The study identifies SLC16A3 as a novel driver of ferroptosis resistance and gefitinib tolerance in lung adenocarcinoma.

## Key findings

- SLC16A3 expression is elevated in LUAD and linked to poor patient outcomes.
- SLC16A3 inhibition enhances ferroptosis and restores EGFR-TKI efficacy in tumor models.
- The HIF1A-SLC16A3 axis regulates ferroptosis resistance and lactate metabolism.

## Abstract

Ferroptosis 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.

We 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.

SLC16A3 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.

Our 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.