Dietary Selenium deficiency activates the NLRP3 inflammasome to induce gallbladder pyroptosis by regulating glycolysis and histone lactylation through ROS/HIF-1α pathway.

Abstract

Selenium (Se) is an essential micronutrient, and inadequate intake can disrupt redox balance in digestive organs, promoting inflammation. Enhanced glycolysis leads to lactate accumulation, exacerbating the inflammatory response through inflammation-related pathways. Histone lysine lactylation plays a key role in epigenetic regulation. The effect of Se deficiency on the gallbladder remains unclear. To explore the mechanism of Se deficiency on gallbladder injury and the regulatory role of histone lactylation, we established Se-deficient swine models and in vitro cell models. Histopathological observation of the gallbladder found that Se deficiency led to inflammatory damage to the gallbladder. Metabolomics and proteomics results showed that Se deficiency led to significant enrichment of "glycolytic flux", "oxidative stress", and "hypoxia-inducible factor-1 α (HIF-1α) signaling pathway". Further studies have found that Se deficiency led to oxidative stress in gallbladder tissue, abnormal expression of HIF-1α factor, increased glycolysis levels, excessive lactate production, increased histone lactylation, and pyroptosis. HIF-1α knockdown suppressed Se deficiency-induced glycolysis and reduced lactate accumulation. In vitro studies using N-acetylcysteine (NAC), 2-deoxyglucose (2-DG), Oxamate and A-485 showed that Reactive oxygen species (ROS) regulated increased glycolysis through HIF-1α and increased H3K18 lactylation (H3K18la) levels through substrate-dependent modifications. Furthermore, H3K18la activated NLRP3 inflammasome, triggering pyroptosis and inflammatory cascades. In conclusion, the results of this study showed that dietary Se deficiency promotes glycolysis-dependent histone lactylation via the ROS/HIF-1α pathway, activating NLRP3 inflammasome, leading to pyroptosis and inflammation in gallbladder. These findings provide insights into targeted therapies for Se deficiency-related metabolic disorders and pathological changes in organs.