The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer

Lung cancer progression is characterized by intricate epigenetic changes that impact critical metabolic processes and cell death pathways. In this study, we investigate the role of histone lactylation at the AIM2 locus and its downstream effects on ferroptosis regulation and lung cancer progression. We utilized a combination of biochemical assays, including chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and western blotting to assess histone lactylation levels and gene expression. To evaluate the functional consequences, we employed gain- and loss-of-function approaches using shikonin treatment and siRNA knockdowns in lung cancer cell lines. Additionally, we assessed the impact of these interventions on ferroptosis markers and lung cancer cell viability. Our results reveal that increased histone lactylation at the AIM2 locus correlates with enhanced transcriptional activity of AIM2, leading to reduced ferroptosis through modulation of ACSL4 and STAT5B. Furthermore, we demonstrate that shikonin, a natural naphthoquinone derivative, effectively downregulates PKM2 and AIM2 expression, thereby inhibiting lung cancer progression by counteracting the effects of histone lactylation on AIM2 expression. These findings highlight the importance of histone lactylation in regulating AIM2 expression and ferroptosis in lung cancer cells. They also suggest that targeting PKM2 and AIM2, particularly through the use of shikonin, could be a promising strategy for developing novel therapies against lung cancer.