Introduction

This study aims to explore how AARS2-mediated histone lactylation affects SLC7A11 expression and ferroptosis in lung cancer cells, and to provide new therapeutic targets.

Material and methods

A549 and H1299 lung cancer cell lines were used. siRNA knocked down AARS2. Western blot, CCK-8, iron detection, flow cytometry, quantitative polymerase chain reaction (qPCR), chromatin immunoprecipitation-qPCR, dual-luciferase reporter assays, and a nude mouse tumour model were applied to analyse the role of AARS2 in ferroptosis in vitro and in vivo.

Results

AARS2 knockdown significantly reduced cell viability (p < 0.001), increased Fe²⁺ and total iron content (p < 0.001), and elevated lipid ROS levels (p < 0.001), indicating enhanced ferroptosis. AARS2 regulated SLC7A11 expression via histone H3K18 lactylation. In animal experiments, AARS2 knockdown inhibited tumour growth (p < 0.001), raised Fe²⁺ and total iron in tumour tissues (p < 0.001), and reduced SLC7A11 expression (p < 0.001), while GPX4 levels showed no significant change (p > 0.05). Mechanistically, decreased H3K18 lactylation weakened epigenetic activation of the SLC7A11 promoter, thus inhibiting SLC7A11 expression.

Conclusions

AARS2 promotes ferroptosis in lung cancer cells by regulating SLC7A11 through histone lactylation. AARS2 may serve as a new target for lung cancer therapy.