Developing diagnostic biomarkers for Alzheimer's disease based on histone lactylation-related gene.

Background: Research underscores the significant influence of histone lactylation pathways in the progression of Alzheimer's disease (AD), though the molecular mechanisms associated with histone lactylation-related genes (HLRGs) in AD are still insufficiently investigated. Methods: This study employed datasets GSE85426 and GSE97760 to identify candidate genes by intersecting weighted gene co-expression network analysis (WGCNA) module genes with AD-control differentially expressed genes (DEGs). Subsequently, machine learning refined key genes, validated by receiver operating characteristic (ROC) curve performance. Gene-set enrichment analysis (GSEA) explored the molecular mechanisms of these diagnostic markers. Concurrently, the association between the diagnostic genes and both differential immune cells and immune responses was examined. Furthermore, a ceRNA and gene-drug network was developed. Finally, the expression of the selected genes was validated using brain tissues from AD model mice. Results: This study identified five genes (ARID5B, NSMCE4A, SESN1, THADA, and XPA) with significant diagnostic utility, primarily enriched in olfactory transduction and N-glycan biosynthesis pathways. Correlation analysis demonstrated a strong positive association between all diagnostic genes and naive B cells. The ceRNA regulatory network comprised 7 miRNAs, 2 mRNAs, and 25 lncRNAs. Additionally, 33 drugs targeting the diagnostic genes were predicted. Following expression validation through training and validation sets, three genes (ARID5B, SESN1, XPA) were ultimately confirmed as biomarkers for this study. RT-qPCR and Western blot analyses revealed upregulated expression of ARID5B, SESN1, and XPA in the cerebral tissue of AD model mice. Conclusion: Three histone lactylation-linked genes (ARID5B, SESN1, XPA) were identified as potential AD biomarkers, indicating a strong association with disease progression.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

BACKGROUND: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. METHODS: To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. RESULTS: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. CONCLUSIONS: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.

Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ T cell exhaustion, and cholesterol-modified siIL11 restores CD8+ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.

The impact of histone lactylation on the tumor microenvironment and metabolic pathways and its potential in cancer therapy.

BACKGROUND: The complexity of cancer is intricately linked to its multifaceted biological processes, including the roles of the tumor microenvironment (TME) as well as genetic and metabolic regulation. Histone lactylation has recently emerged as a novel epigenetic modification mechanism that plays a pivotal role in regulating cancer initiation, proliferation, invasion, and metastasis. OBJECTIVE: This review aims to elucidate the role of histone lactylation in modulating various aspects of tumor biology, including DNA repair mechanisms, glycolytic metabolic abnormalities, functions of non-tumor cells in the TME, and the promotion of tumor inflammatory responses and immune escape. Additionally, the review explores potential therapeutic strategies targeting histone lactylation. METHODS: A comprehensive literature review was performed, analyzing recent findings on histone lactylation and its impact on cancer biology. This involved a systematic examination of studies focusing on biochemical pathways, cellular interactions, and clinical implications related to histone lactylation. RESULTS: Histone lactylation was identified as a critical regulator of tumor cell DNA repair mechanisms and glycolytic metabolic abnormalities. It also significantly influences the functions of non-tumor cells within the TME, promoting tumor inflammatory responses and immune escape. Moreover, histone lactylation acts as a multifunctional biological signaling molecule impacting immune responses within the TME. Various cell types within the TME, including T cells and macrophages, were found to regulate tumor growth and immune escape mechanisms through lactylation. CONCLUSION: Histone lactylation offers a novel perspective on tumor metabolism and its role in cancer development. It presents promising opportunities for the development of innovative cancer therapies. This review underscores the potential of histone lactylation as a therapeutic target, paving the way for new strategies in cancer treatment.

TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation.

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis. METHODS: TRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT-qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated ß-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis. RESULTS: VSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo. CONCLUSIONS: This study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.

LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene.

Osteoarthritis (OA) is a worldwide joint disease, leading to the physical pain, stiffness, and even disability. Lactate dehydrogenase A (LDHA) is known as a lactylation mediator that can regulate histone lactylation of its target genes. However, the role of LDHA-mediated histone H3 lysine 18 lactylation (H3K18la) in OA progression is yet to be clarified. Our study aims at revealing the role and mechanism of LDHA-mediated histone lactylation in the glycolysis of chondrocytes. In this study, we determined at first that the H3K18la level was enhanced in OA. Energy metabolism such as glycolysis is often altered in OA progress. Therefore, we further explored the mechanism mediating glycolysis and thus promoting OA progress. Moreover, glycolysis was enhanced in LPS-induced OA cell model, as evidenced by the increased glucose consumption and lactate production. Furthermore, we silenced LDHA for loss-of-function assays. The results showed that knockdown of LDHA suppressed glycolysis of LPS-induced chondrocytes. In vivo animal study demonstrated that knockout of LDHA recovered cartilage injury of OA mice. Mechanistically, we uncovered that LDHA-mediated H3K18la in TPI1 promoter enhanced the transcription activity of TPI1. Mutation of K69 site was found to ameliorate LPS-induced glycolysis in OA cell model. In conclusion, our study reveals the role of LDHA-mediated H3K18la of TPI1 promoter in OA progress.

AST-120 alleviates renal ischemia-reperfusion injury by inhibiting HK2-mediated glycolysis.

OBJECTIVE: Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism. METHODS: A renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation. RESULTS: The results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown. CONCLUSIONS: In conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI.

Physical exercise mediates cortical synaptic protein lactylation to improve stress resilience.

Lactate is a critical metabolite during the body's adaption to exercise training, which effectively relieves anxiety-like disorders. The biological mechanism of lactate in the exercise-mediated anxiolytic effect has, however, not been comprehensively investigated. Here, we report that exercise-induced lactate markedly potentiates the lactylation of multiple synaptic proteins, among which synaptosome-associated protein 91 (SNAP91) is the critical molecule for synaptic functions. Both anatomical evidence and in vivo recording data showed that the lactylation of SNAP91 confers resilience against chronic restraint stress (CRS) via potentiating synaptic structural formation and neuronal activity in the medial prefrontal cortex (mPFC). More interestingly, exercise-potentiated lactylation of SNAP91 is necessary for the prevention of anxiety-like behaviors in CRS mice. These results collectively suggest a previously unrecognized non-histone lactylation in the brain for modulating mental functions and provide evidence for the brain's metabolic adaption during exercise paradigms.

Histone lactylation dynamics: Unlocking the triad of metabolism, epigenetics, and immune regulation in metastatic cascade of pancreatic cancer.

Cancer cells rewire metabolism to sculpt the immune tumor microenvironment (TME) and propel tumor advancement, which intricately tied to post-translational modifications. Histone lactylation has emerged as a novel player in modulating protein functions, whereas little is known about its pathological role in pancreatic ductal adenocarcinoma (PDAC) progression. Employing a multi-omics approach encompassing bulk and single-cell RNA sequencing, metabolomics, ATAC-seq, and CUT&Tag methodologies, we unveiled the potential of histone lactylation in prognostic prediction, patient stratification and TME characterization. Notably, "LDHA-H4K12la-immuno-genes" axis has introduced a novel node into the regulatory framework of "metabolism-epigenetics-immunity," shedding new light on the landscape of PDAC progression. Furthermore, the heightened interplay between cancer cells and immune counterparts via Nectin-2 in liver metastasis with elevated HLS unraveled a positive feedback loop in driving immune evasion. Simultaneously, immune cells exhibited altered HLS and autonomous functionality across the metastatic cascade. Consequently, the exploration of innovative combination strategies targeting the metabolism-epigenetics-immunity axis holds promise in curbing distant metastasis and improving survival prospects for individuals grappling with challenges of PDAC.

Lactate modulates zygotic genome activation through H3K18 lactylation rather than H3K27 acetylation.

In spite of its essential role in culture media, the precise influence of lactate on early mouse embryonic development remains elusive. Previous studies have implicated lactate accumulation in medium affecting histone acetylation. Recent research has underscored lactate-derived histone lactylation as a novel epigenetic modification in diverse cellular processes and diseases. Our investigation demonstrated that the absence of sodium lactate in the medium resulted in a pronounced 2-cell arrest at the late G2 phase in embryos. RNA-seq analysis revealed that the absence of sodium lactate significantly impaired the maternal-to-zygotic transition (MZT), particularly in zygotic gene activation (ZGA). Investigations were conducted employing Cut&Tag assays targeting the well-studied histone acetylation and lactylation sites, H3K18la and H3K27ac, respectively. The findings revealed a noticeable reduction in H3K18la modification under lactate deficiency, and this alteration showed a significant correlation with changes in gene expression. In contrast, H3K27ac exhibited minimal correlation. These results suggest that lactate may preferentially influence early embryonic development through H3K18la rather than H3K27ac modifications.

Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT.

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients' arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on Apoe KO Asf1a ECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

Gegen Qinlian decoction inhibited M1 macrophage polarization and ulcerative colitis progression through regulating histone lactylation.

Ulcerative colitis (UC) is a persistent inflammatory condition affecting the bowels. Gegen Qinlian decoction (GQD) has been widely used in the therapy of gastrointestinal diseases. We investigated the protective impacts and mechanism of GQD against UC. To establish the UC model, dextran sulfate sodium (DSS) was utilized. The disease activity index (DAI), colon length and colonic pathology were assessed to examine the impacts of GQD on UC. The level of pan-lysine lactylation (Pan kla) and specific sites were detected using western blot. Then, the inflammatory factors and the oxidative stress parameters were measured via the corresponding kits, respectively. Our findings demonstrated that GQD suppressed the lactate generation and LDH activity. The western blot revealed that GQD inhibited the expression of Pan kla and specific sites of H3K18la, H3K23la, H4K8la, and H4K12la. Furthermore, the suppressive effects on inflammation and oxidative stress caused by GQD were counteracted upon the exogenous lactate. GQD suppressed the phenotypic differentiation of M1 macrophages by reducing the expression of M1 markers, which was also reversed by exogenous lactate. In conclusion, GQD effectively suppressed UC progression through histone lactylation. Our results broadened the theoretical basis for the clinical use of GQD.

Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage.

Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation of substantial amounts of lactate to maintain the energy demand for neurons and other brain cells. Lactate has garnered increasing attention in recent years because of its emerging role in critical biological processes such as inflammation regulation and neuroprotection, particularly through its histone lactylation. Bromodomain-containing protein 4 (BRD4) plays a crucial role in maintaining neural development and promoting memory formation in the central nervous system. Nonetheless, the function and regulatory mechanism of BRD4 and histone lactylation in astrocytes following SAH remain elusive. Our findings indicate that BRD4, a crucial epigenetic regulator, plays a definitive role in histone lactylation. Both in vitro and in vivo, these results demonstrated that targeted silencing of BRD4 in astrocytes can significantly reduce H4K8la lactylation, thereby aggravating the A1 polarization of astrocytes and ultimately affecting the recovery of neural function and prognosis in mice after SAH. In summary, BRD4 plays a pivotal role in modulating astrocyte polarization following SAH via histone lactylation. Targeting this mechanism might offer an efficient therapeutic strategy for SAH.

Histone lactylation-related genes correlate with the molecular patterns and functions of cancer-associated fibroblasts and have significant clinical implications in clear cell renal cell carcinoma.

Recent research emphasised the indispensable role of histone lactylation in the activation of hepatic stellate cells. The VHL mutation is extremely common in clear cell renal cell carcinoma, which normally causes a metabolic shift in cancer cells and increases lactate production, eventually creating a lactate-enriched tumour microenvironment. Cancer-associated fibroblasts (CAFs) promote tumour progression, which is also vital in clear cell renal cell carcinoma. Therefore, this study investigated histone lactylation in CAFs and its impact on patient survival. Multiomics technology was employed to determine the role of histone lactylation-related genes in the evolution of CAFs which correlated with the function and molecular signatures of CAFs. The results suggested that TIMP1 was the hub gene of histone lactylation-related genes in clear cell renal cell carcinoma.

Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury.

Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a leading cause of poor prognosis in clinical patients. However, the underlying mechanisms of lactate's involvement in sepsis-associated ALI remain unclear. In this study, we demonstrate that lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. The METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Furthermore, short-term lactate stimulation upregulates ACSL4, which promotes mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. Our findings suggest that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These results reveal a histone lactylation-driven mechanism inducing ferroptosis through METTL3-mediated m6A modification. Targeting METTL3 represents a promising therapeutic strategy for patients with sepsis-associated ALI.

H3K18 lactylation accelerates liver fibrosis progression through facilitating SOX9 transcription.

Liver fibrosis is a significant health concern globally due to its association with severe liver conditions like cirrhosis and liver cancer. Histone lactylation has been implicated in the progression of hepatic fibrosis, but its specific role in liver fibrosis, particularly regarding H3K18 lactylation, remained unclear. To investigate this, we established in vivo and in vitro models of liver fibrosis using carbon tetrachloride (CCl4) injection in rats and stimulation of hepatic stellate cells (HSCs) with TGF-ß1, respectively. We found that histone lactylation, particularly H3K18 lactylation, was upregulated in both CCl4-induced rats and TGF-ß1-activated HSCs, indicating its potential involvement in liver fibrosis. Further experiments revealed that lactate dehydrogenase A (LDHA) knockdown inhibited H3K18 lactylation and had a beneficial effect on liver fibrosis by suppressing HSC proliferation, migration, and extracellular matrix (ECM) deposition. This suggests that H3K18 lactylation promotes liver fibrosis progression. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that H3K18 lactylation facilitated the transcription of SOX9, a transcription factor associated with fibrosis. Importantly, overexpression of SOX9 counteracted the effects of LDHA silencing on activated HSCs, indicating that SOX9 is downstream of H3K18 lactylation in promoting liver fibrosis. In summary, this study uncovers a novel mechanism by which H3K18 lactylation contributes to liver fibrosis by activating SOX9 transcription. This finding opens avenues for exploring new therapeutic strategies for hepatic fibrosis targeting histone lactylation pathways.

Virus-Induced Histone Lactylation Promotes Virus Infection in Crustacean.

As "non-cellular organisms", viruses need to infect living cells to survive themselves. The virus infection must alter host's metabolisms. However, the influence of the metabolites from the altered metabolisms of virus-infected host cells on virus-host interactions remains largely unclear. To address this issue, shrimp, a representative species of crustaceans, is challenged with white spot syndrome virus (WSSV) in this study. The in vivo results presented that the WSSV infection enhanced shrimp glycolysis, leading to the accumulation of lactate. The lactate accumulation in turn promoted the site-specific histone lactylation (H3K18la and H4K12la) in a p300/HDAC1/HDAC3-dependent manner. H3K18la and H4K12la are enriched in the promoters of 75 target genes, of which the H3K18la and H4K12la modification upregulated the expression of ribosomal protein S6 kinases 2 (S6K2) in the virus-infected hosts to promote the virus infection. Further data revealed that the virus-encoded miR-N20 targeted hypoxia inducible factor-1α (HIF-1α) to inhibit the host glycolysis, leading to the suppression of H3K18la and H4K12la. Therefore, the findings contributed novel insights into the effects and the underlying mechanism of the virus-induced histone lactylation on the virus-host interactions, providing new targets for the control of virus infection.

LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma.

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.