Project description:Despite that lactate accumulation is deemed to be a marker of severe sepsis, lactate-driven histone lactylation induces transcription of homeostatic genes. Thus, the biological roles of lactate in sepsis remain unknown. Here, we report that amlexanox, an anti-inflammatory drug, improves survival, mitigates multiorgan dysfunction, and suppresses inflammatory infiltrates in endotoxemia and sepsis. Mechanistically, amlexanox elevates intracellular lactate to enhance histone lactylation of IL10 gene promoter and IL-10 production to alleviate sepsis. Blocking IL-10 receptor nearly abrogates therapeutic effect of amlexanox, and inhibiting lactate production abrogates amlexanox-induced IL-10. Amlexanox treatment significantly downregulates gene expression of electron transport chain, indicating it elevates lactate level by breaking aerobic respiration. Importantly, in vivo sodium lactate administration improves survival in endotoxemia. Our study clarifies that elevating lactate-mediated histone lactylation plays a protective role in sepsis, and amlexanox is a potential drug for sepsis.
Project description:The pathogenesis of cancer is rather complicated and includes multiple aspects, with metabolic reprogramming and angiogenesis as the leading hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation level to epigenetically regulate gene expressions and biological processes in cancer, while the role of lactate-mediated histone lactylation in tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we demonstrate that lactate-mediated histone lactylation promotes tumor angiogenesis via IL-33/ST2 axis.
Project description:Lactic acidosis, driven by hyperlactatemia, is a hallmark of severe Plasmodium falciparum malaria, yet its impact on parasitic life cycle and gene expression remains unclear. In mammalian cells, lactate influences transcription through histone lactylation, a novel post-translational modification. In this study, we demonstrate that P. falciparum undergoes lactate-derived lysine lactylation on nuclear proteins, including histones, histone variants, and AP2 transcription factors, with lactylation levels dynamically varying in response to physiological lactate ranges. Through CUT&RUN profiling, we show that elevated lactate enhances chromatin occupancy of lactylated proteins at promoters of genes involved in virulence and cytoadherence. Correspondingly, transcriptomic analyses demonstrated a suppression of these genes in response to elevated lactate, a pattern also evident in clinical isolates from severe malaria patients. Functionally, we demonstrate that high lactate reduces the binding ability of infected erythrocytes to CD36 receptor. Together, our findings reveal protein lactylation as a metabolite-responsive epigenetic mechanism in P. falciparum, linking host metabolic state to transcriptional reprogramming with direct implications for parasite virulence and disease pathogenesis.
Project description:Chronic wounds, characterized by delayed healing and persistent inflammation, represent a major clinical burden with limited effective therapies. Inspired by the stereoselective interactions in biological systems, we developed an L-chiral hydrogel composed of self-assembled helical nanofibers from L-histidine derivatives, which preferentially enriches lactate to promote wound repair. Compared to D-chiral and racemic hydrogels, the L-chiral hydrogel significantly accelerated wound closure in rat models, achieving nearly 90% healing by day 14 and reducing healing time to 16-17 days. Transcriptomic and metabolomic analyses revealed enhanced wound response pathways and elevated lactate levels in the L-chiral group. Mechanistically, enriched lactate induced K57 lactylation of RNF123, mediated by AARS1, altering RNF123 conformation and weakening its binding to UBAC1. This modification enhanced ubiquitination and processing of NF-κB p105 into p50, inhibiting the NF-κB pathway and promoting angiogenesis via enhanced endothelial cell migration, tube formation, and sprouting. Rescue experiments with lactate inhibitor Oxamate and exogenous lactate confirmed the lactate-dependent mechanism. This study not only demonstrates a drug-free chiral biomaterial for efficient wound healing but also unveils the molecular role of lactate-mediated lactylation in mechanoregulating inflammation and vascularization, offering new insights for regenerative medicine.
Project description:Sepsis is characterized by lactate accumulation and immune dysfunction, but the molecular mechanisms linking lactate to chemokine expression remain unclear. Here, we investigated whether lactate regulates chemokine transcription through histone lactylation. Human peripheral blood mononuclear cells (PBMCs) were treated with lactate (LAC group) or PBS control (CON group), followed by RNA sequencing (RNA-seq) to identify differentially expressed genes. Chromatin immunoprecipitation sequencing (ChIP-seq) using H3K18la-specific antibody was performed to detect lactylation-enriched gene promoters. Integration of RNA-seq and ChIP-seq data identified CX3CL1 as a lactylation-regulated chemokine. Functional assays demonstrated that lactate-induced H3K18la promotes CX3CL1 expression, enhances PBMC migration, and facilitates T cell recruitment in vitro. In a cecal ligation and puncture (CLP)-induced sepsis-associated acute respiratory distress syndrome (ARDS) mouse model, elevated lactate increased pulmonary CX3CL1 expression and immune cell infiltration, whereas inhibition of lactate production reduced these effects. These data reveal a lactate–H3K18la–CX3CL1 axis that mediates immune cell recruitment and exacerbates sepsis-related lung injury.
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.
Project description:Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades anti-tumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming towards glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of microglial phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) P300 to induce increased P300 substrate specificity toward lactyl-coA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates a metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immune-oncology therapies.