H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP

Wang, Peiwen; Xie, Daxiao; Xiao, Tian; Cheng, Cheng; Wang, Dapeng; Sun, Jing; Wu, Meng; Yang, Yi; Zhang, Aihua; Liu, Qizhan

doi:10.1016/j.jhazmat.2023.132582

Cited by 16 publications

(7 citation statements)

References 87 publications

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“…ChIP-seq and CUT&Tag assays were employed to ascertain the binding affinity of lactate modification towards relevant genes [ 46 , 47 ]. Notably, the presence of H3K18 lactylation in pulmonary fibrosis was found to enhance the transcription of YTHDF1 [ 48 ]. We found via ChIP-qPCR experiments that Sal B can reduce the levels of H3K18la in the promoter region of the M1 macrophage glycolysis-related gene LDHA and the inflammation-related genes NLRP3 and IL-1β, suggesting that Sal B can reduce endogenous lactate-mediated histone lactylation modifications in M1 macrophages, which, in turn, upregulates the expression of genes.…”

Section: Discussionmentioning

confidence: 99%

“…In the past few years, histone lactylation has been introduced as a newly identified modification and has been strongly linked to various fibrotic conditions [ 48 , 49 , 50 , 51 ]. Similar to liver fibrosis, histone lactylation modifications are elevated in both alveolar macrophages of pulmonary fibrosis and placental fibrosis [ 49 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

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Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

Hu,

Yang,

et al. 2024

Molecules

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Salvianolic acid B (Sal B) is the primary water-soluble bioactive constituent derived from the roots of Salvia miltiorrhiza Bunge. This research was designed to reveal the potential mechanism of Sal B anti-liver injury from the perspective of macrophages. In our lipopolysaccharide-induced M1 macrophage model, Sal B showed a clear dose-dependent gradient of inhibition of the macrophage trend of the M1 type. Moreover, Sal B downregulated the expression of lactate dehydrogenase A (LDHA), while the overexpression of LDHA impaired Sal B’s effect of inhibiting the trend of macrophage M1 polarization. Additionally, this study revealed that Sal B exhibited inhibitory effects on the lactylation process of histone H3 lysine 18 (H3K18la). In a ChIP-qPCR analysis, Sal B was observed to drive a reduction in H3K18la levels in the promoter region of the LDHA, NLRP3, and IL-1β genes. Furthermore, our in vivo experiments showed that Sal B has a good effect on alleviating CCl4-induced liver injury. An examination of liver tissues and the Kupffer cells isolated from those tissues proved that Sal B affects the M1 polarization of macrophages and the level of histone lactylation. Together, our data reveal that Sal B has a potential mechanism of inhibiting the histone lactylation of macrophages by downregulating the level of LDHA in the treatment of liver injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

Hu,

Yang,

et al. 2024

Molecules

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“…Zhao et al [ 32 ] highlighted SLC16A1 as a prognostic marker in osteosarcoma, where its downregulation inhibited tumor growth and enhanced chemotherapy efficacy[ 32 ]. Further studies have indicated that SLC16A1 influences overall cellular lactate levels and disease progression[ 19 , 33 , 34 ]. The HLA system is the major histocompatibility complex in humans, believed to be related to the occurrence and development of various tumors, and has always been a focal point in tumor immunology research[ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

Peng,

Sun,

Yang

et al. 2024

World J Gastroenterol

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BACKGROUND Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package “DESeq2” in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL ) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/ Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.

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“…Myofibroblast glycolysis induces p300-mediated histone lactylation and the expression of profibrotic genes in lung macrophages, thereby contributing to the pathogenesis of lung fibrosis ( Cui et al, 2021 ). The crosstalk between alveolar epithelial cells and myofibroblasts through H3K18la facilitates the progression of arsenite-induced idiopathic pulmonary fibrosis ( Wang et al, 2024 ). During hepatic stellate cell activation, hexokinase 2 (HK2) has been found to induce liver fibrosis by promoting histone lactylation ( Rho et al, 2023 ).…”

Section: Function Of Protein Lactylationmentioning

confidence: 99%

Lactylation: The emerging frontier in post-translational modification

Lu,

Zheng,

Shi

et al. 2024

Front. Genet.

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Lactate, a metabolic byproduct, has gained recognition as a highly influential signaling molecule. Lactylation, an emerging form of post-translational modification derived from lactate, plays a crucial role in numerous cellular processes such as inflammation, embryonic development, tumor proliferation, and metabolism. However, the precise molecular mechanisms through which lactylation governs these biological functions in both physiological and pathological contexts remain elusive. Hence, it is imperative to provide a comprehensive overview of lactylation in order to elucidate its significance in biological processes and establish a foundation for forthcoming investigations. This review aims to succinctly outline the process of lactylation modification and the characterization of protein lactylation across diverse organisms. Additionally, A summary of the regulatory mechanisms of lactylation in cellular processes and specific diseases is presented. Finally, this review concludes by delineating existing research gaps in lactylation and proposing primary directions for future investigations.

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H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP

Cited by 16 publications

References 87 publications

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

Lactylation: The emerging frontier in post-translational modification

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