H3K9/18 lactylation regulates DNA damage due to nickel exposure in human bronchial epithelial cells.

Nickel, a well-known heavy metal with lung carcinogenic properties, is recognized for its effects on cellular metabolism, oxidative stress, and gene expression. While these cellular alterations have prompted investigations into its potential impact on histone modifications, specific associations with histone lactylation remain under exploration. In the present study, we demonstrate that nickel exposure induces lactylation of histone H3 at lysines 9 (H3K9) and 18 (H3K18), accompanied by reactive oxygen species (ROS) accumulation and DNA damage in human bronchial epithelial Beas-2B cells. Inhibition of H3K9 and H3K18 lactylation, achieved by overexpressing mutated H3K9R and H3K18R, respectively, markedly abolishes ROS generation and DNA damage caused by nickel exposure. This highlights the novel biological effects of H3K9 and H3K18 lactylation in nickel-induced lung toxicity. Mechanistic investigations show that nickel-induced lactylation of H3K9 and H3K18 is mediated by elevated LDHA expression, leading to lactate accumulation, which results from the upregulation of LDHA mRNA transcription through HIF-1α/c-Jun axis and enhanced LDHA protein stability via TNF-α-mediated induction of HSP70, respectively. Our findings uncover a novel effect of nickel exposure on histone H3 lactylation and its biological impact on ROS accumulation and DNA damage through the HIF-1α/c-Jun/LDHA and TNF-α/HSP70/LDHA pathways. These results provide significant insights into the role of histone lactylation in heavy metal-induced lung toxicity.