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BackgroundIschemic stroke is a common and severe cerebrovascular disease with high mortality and disability. Accumulating evidence indicates that β-caryophyllene (BCP) exerts neuroprotective effects against cerebral ischemic injury; however, the precise underlying mechanisms remain largely unexplored.MethodsFocal cerebral ischemia/reperfusion (I/R) mouse models were established in vivo and oxygen-glucose deprivation/reoxygenation (OGD/R) was conducted in BV2 microglial cells and primary microglia in vitro.ResultsWe demonstrated that BCP administration significantly reduced cerebral infarct volume, alleviated neurological deficits, and enhanced motor function in mice subjected to transient focal cerebral ischemia. Mechanistically, BCP inhibited pyroptosis and glycolysis in the ischemic penumbra of mice and in BV2 cells following OGD/R. Concomitantly, BCP decreased the levels of H3K9 lactylation (H3K9la) and H3K18 lactylation (H3K18la) in brain tissues of ischemic penumbra and in OGD/R-induced BV2 cells. Notably, co-treatment with lactate attenuated these inhibitory effects and abrogated the neuroprotective efficacy of BCP. Similar results were also obtained in primary microglia. Additionnaly, oxamate (the LDHA inhibitor) simultaneously downregulated the protein levels of H3K9la, H3K18la, and pyroptosis-related factors, while MCC950 (the NLRP3 inflammasome inhibitor) only blocked downstream pyroptosis without affecting histone lactylation. Chip-PCR further demonstrated that OGD/R increased the enrichment of H3K9la and H3K18la at the NLRP3 promoter, which was decreased by BCP and oxamate but not by MCC950. Lactate supplementation partially restored the inhibitory effects of BCP.ConclusionBCP protects against ischemic stroke by targeting the lactate-histone lactylation-pyroptosis axis, providing a potential therapeutic target for cerebral ischemia.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor associated with high morbidity and mortality. Therefore, it is of great importance to develop effective prognostic models and guide clinical treatment in HCC. Protein lactylation is found in HCC tumors and is associated with HCC progression. Methods: The expression levels of lactylation-related genes were identified from the TCGA database. A lactylation-related gene signature was constructed using LASSO regression. The prognostic value of the model was assessed and further validated in the ICGC cohort, with the patients split into two groups based on risk score. Glycolysis and immune pathways, treatment responsiveness, and the mutation of signature genes were analyzed. The correlation between PKM2 expression and the clinical characteristics was investigated. Results: Sixteen prognostic differentially expressed lactylation-related genes were identified. An 8-gene signature was constructed and validated. Patients with higher risk scores had poorer clinical outcomes. The two groups were different in immune cell abundance. The high-risk group patients were more sensitive to most chemical drugs and sorafenib, while the low-risk group patients were more sensitive to some targeted drugs such as lapatinib and FH535. Moreover, the low-risk group had a higher TIDE score and was more sensitive to immunotherapy. PKM2 expression correlated with clinical characteristics and immune cell abundance in the HCC samples. Conclusions: The lactylation-related model exhibited robust predictive efficiency in HCC. The glycolysis pathway was enriched in the HCC tumor samples. A low-risk score indicated better treatment response to most targeted drugs and immunotherapy. The lactylation-related gene signature could be used as a biomarker for the effective clinical treatment of HCC.

Histone lactylation is critically involved in the regulation of gene expression and the modulation of diverse cellular processes in both normal and tumor cells. A recent study by Zhu et al. [Cell Metab. 37 , 361–376] demonstrated that ACSS2 functions as a bona fide lactyl-CoA synthetase, converting lactate into lactyl-CoA. In response to elevated aerobic glycolysis and EGFR activation, ERK-mediated phosphorylation drives the nuclear translocation of ACSS2, promoting the formation of the ACSS2–KAT2A complex. KAT2A utilizes ACSS2-derived lactyl-CoA and acts as a lactyltransferase to promote histone lactylation, gene expression, tumor growth, and immune evasion.

The Warburg Effect is one of the most well-known cancer hallmarks. This metabolic pattern centered on lactate has extremely complex effects on various aspects of tumor microenvironment, including metabolic remodeling, immune suppression, cancer cell migration, and drug resistance development. Based on accumulating evidence, metabolites are likely to participate in the regulation of biological processes in the microenvironment and to form a feedback loop. Therefore, further revealing the key mechanism of lactate-mediated oncological effects is a reasonable scientific idea. The discovery and refinement of histone lactylation in recent years has laid a firm foundation for the above idea. Histone lactylation is a post-translational modification that occurs at lysine sites on histones. Specific enzymes, known as \"writers\" and \"erasers\", catalyze the addition or removal, respectively, of lactacyl group at target lysine sites. An increasing number of investigations have reported this modification as key to multiple cellular procedures. In this review, we discuss the close connection between histone lactylation and a series of biological processes in the tumor microenvironment, including tumorigenesis, immune infiltration, and energy metabolism. Finally, this review provides insightful perspectives, identifying promising avenues for further exploration and potential clinical application in this field of research.

Mortality rates due to lung cancer are high worldwide. Although PD‐1 and PD‐L1 immune checkpoint inhibitors boost the survival of patients with non‐small‐cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build‐up and potential lysine‐lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non‐histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi‐omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl‐APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti‐APOC2K70‐lac antibody that sensitized anti‐PD‐1 therapy in vivo is developed. This findings highlight the potential of anti lactyl‐APOC2‐K70 approach as a new combination therapy for sensitizing immunotherapeutic responses. Although PD‐1/PD‐L1 immune‐checkpoint inhibitors boost the survival of patients with NSCLC, resistance often arises. Combining global lactylome profiling, metabolomics and mechanistic‐experiments, it is found that intracellular lactate promotes extracellular lipolysis through lactyl‐APOC2‐K70, inducing Tregs accumulation and immunotherapy resistance. An anti‐APOC2K70‐lac antibody that sensitized anti‐PD‐1 therapy in vivo is developed. This findings suggest that targeting lactylated APOC2‐K70 could improve the effectiveness of immunotherapy.

Lactate is an end product of glycolysis. As a critical energy source for mitochondrial respiration, lactate also acts as a precursor of gluconeogenesis and a signaling molecule. We briefly summarize emerging concepts regarding lactate metabolism, such as the lactate shuttle, lactate homeostasis, and lactate-microenvironment interaction. Accumulating evidence indicates that lactate-mediated reprogramming of immune cells and enhancement of cellular plasticity contribute to establishing disease-specific immunity status. However, the mechanisms by which changes in lactate states influence the establishment of diverse functional adaptive states are largely uncharacterized. Posttranslational histone modifications create a code that functions as a key sensor of metabolism and are responsible for transducing metabolic changes into stable gene expression patterns. In this review, we describe the recent advances in a novel lactate-induced histone modification, histone lysine lactylation. These observations support the idea that epigenetic reprogramming-linked lactate input is related to disease state outputs, such as cancer progression and drug resistance.

Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, and it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), a neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests that senescent microglia play a role in the pathogenesis of AD, their exact role remains unclear. In this study, we quantified the levels of lactic acid in senescent microglia, and hippocampus tissues of naturally aged mice and AD mice models (FAD 4T and APP/PS1). We found lactic acid levels were significantly elevated in these cells and tissues compared to their corresponding counterparts, which increased the level of pan histone lysine lactylation (Kla). We aslo identified all histone Kla sites in senescent microglia, and found that both the H3K18 lactylation (H3K18la) and Pan-Kla were significantly up-regulated in senescent microglia and hippocampus tissues of naturally aged mice and AD modeling mice. We demonstrated that enhanced H3K18la directly stimulates the NFκB signaling pathway by increasing binding to the promoter of Rela (p65) and NFκB1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 and IL-8. Our study provides novel insights into the physiological function of Kla and the epigenetic regulatory mechanism that regulates brain aging and AD. Specifically, we have identified the H3K18la/NFκB axis as a critical player in this process by modulating IL-6 and IL-8. Targeting this axis may be a potential therapeutic strategy for delaying aging and AD by blunting SASP.

Background Lactylation modification has been reported to increase protein function and regulation complexity. However, mechanisms underlying lactylation in heart failure (HF) remain incompletely understood. Methods We analyzed the GSE57338 through differential expression analysis and WGCNA to identify HF-associated genes, which were intersected with known lactylation-related genes (LRGs) to identify potential LRGs in HF. Consensus clustering identified lactylation-associated clusters. We profiled molecular and immune features of patient subtypes using GSVA and CIBERSORT. We compared machine learning models (RF, SVM, GLM) and developed a nomogram, validating it with GSE5406 and in vivo experiments. Results Intersection analysis identified MYH6 and HSPA2 as the two key LRGs in HF. Consensus clustering revealed two distinct clusters, showing different metabolic features. Immune analysis revealed a positive correlation between HSPA2 and CD8+ T cells, and between MYH6 and M2 macrophages. GLM exhibited better fitting performance than RF and SVM. Finally, the nomogram demonstrated robust predictive performance (AUC > 0.8) in both training and validation set. Notably, HSPA2 was identified as significantly upregulated in HF. Conclusion Our study identified two key LRGs in HF (MYH6 and HSPA2) and established an HF prediction nomogram. The identification of HSPA2 as a promising target suggests a novel clinical strategy for HF.