INTRODUCTION: Aggregation of hyperphosphorylated tau (tauopathy) is associated with cognitive impairment in patients with Alzheimer's disease (AD). In AD, a metabolic shift due to the Warburg effect results in increased lactate production. Lactate can induce a post‐translational modification (PTM) on proteins that conjugates lactyl groups to lysine (K) residues, which is known as lactylation. METHODS: We analyzed lactylation of tau in control and AD brain tissue and conducted cell‐based assays. In addition, we used in vitro assays to determine whether p300 catalyzed tau lactylation. RESULTS: Quantitative proteomics detected that tau lactylation was elevated in AD brains, with K residue at position 331 (K331) being a prominent site. Lactate induced tau lactylation, which increased tau phosphorylation and cleavage and reduced ubiquitination. Inhibition of lactate production lowered tau lactylation; p300 catalyzed tau lactylation. DISCUSSION: Our findings suggest that tau lactylation links metabolic dysregulation with tauopathy and could serve as a novel diagnostic and therapeutic target. Highlights: Elevated tau lactylation, particularly at K331, is evident in in human AD brain samples. Lactate induces tau lactylation, enhancing phosphorylation and cleavage while inhibiting ubiquitination. The acetyl‐transferase p300 catalyzes tau lactylation, with K331 being the most prominent site.

Male germ cells, which are responsible for producing millions of genetically diverse sperm through meiosis in the testis, rely on lactate as their central energy metabolite. Recent study has revealed that lactate induces epigenetic modification in cells through histone lysine lactylation. Here, we report dynamic histone lactylation at histone H4-lysine 5 (K5), -K8, and -K12 during meiosis prophase I in mouse spermatogenesis. By profiling the genome-wide occupancy of histone H4-K8 lactylation (H4K8la), which peaks at zygotene, our data show that H4K8la mark is observed at the promoters of genes exhibiting active expression with Gene Ontology functions enriched for meiosis. Notably, our data also demonstrate that H4K8la is closely associated with recombination hotspots, where machinery involved in the processing DNA double-stranded breaks, such as SPO11, DMC1, RAD51, and RPA2, is engaged. In addition, H4K8la was also detected at the meiosis-specific cohesion sites (marked by RAD21L and REC8) flanking the recombination hotspots. Functionally, our data show that lactate induces upregulation of key meiotic genes through H4K8la modifications. Additionally, H4K8la shows colocalization and interaction with PRDM9 at recombination hotspots. Finally, our data show that HBO1, a lactyltransferase, is highly expressed in meiotic germ cells. In vitro lactylation assays reveal that HBO1 induces H4K8la, and pharmacological inhibition of HBO1 in mice reduces H4K8la levels and disrupts meiosis. Collectively, our findings suggest that histone lactylation serves as an epigenetic mechanism that is involved in meiotic gene expression and recombination in male germ cells during spermatogenesis.

From yeasts to mammals, the molecular machinery and chromosome structures carrying out meiosis are frequently conserved. However, the signal to initiate meiosis appears divergent: while nutrient restriction induces meiosis in the yeast system, retinoic acid (RA), a chordate morphogen, is necessary but not sufficient to induce meiotic initiation in mammalian germ cells via its target, Stra8 . Here, using cultured mouse male germline stem cells without the support of gonadal somatic cells, we show that nutrient restriction in combination with RA robustly induces Spo11 -dependent meiotic DNA double strand breaks (DSBs) and Stra8 -dependent meiotic gene programs recapitulating those of early meiosis in vivo . Moreover, a distinct network of 11 nutrient restriction-upregulated transcription factor genes was identified, whose expression does not require RA and is associated with early meiosis in vivo . Thus, our study proposes a conserved model, in which nutrient restriction induces meiotic initiation by upregulating transcriptional factors for meiotic gene programs, and provides an in vitro platform to derive haploid gametes in culture. One Sentence Summary: nutrient restriction synergizes with retinoic acid to induce mammalian meiotic initiation

The molecular machinery of ovarian aging and female age-related pathway remain unclear. Here, we utilized single-cell RNA-seq to profile over 9815 cells from both young and old female mouse and identified age-related alterations in the female somatic microenvironment. Interestingly, by aging-related signature calculation, we examined HIF1A in mouse ovarian cell aging regulated roles which effect pathways included glycolysis, TCA, OXPHOS and fatty acid metabolism. Additionally, inactivated HIF1A, decreased glycolysis was observed. Comparison analysis reveals the aging related regulon; metabolic and nutrient absorption changes provides a comprehensive understanding of the cell-type-specific mechanisms underlying mouse ovarian aging at single-cell resolution. This study, revealing new potential candidate biomarkers for the diagnosis of aging-associated ovary pathology.

/SUMMARY: The transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8 -driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1 ). Germ cell–specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene.