Funding Lactate and lactylation form a biologically important but context-dependent regulatory network in SA-AKI

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 4 journals. Those papers have been cited 20 times in total.

Supporting evidence — 4 representative gaps

• When metabolic enzymes meet lactylation: a bidirectional dialogue in health and disease (2026) · Frontiers in Cell and Developmental Biology · doi

  frontier research Since the discovery of protein lactylation in 2019 (Zhang et al., lactate-derived post-translational modification has 2019), this emerged as a cutting-edge in biology. Lactylation alters protein conformation, charge, and molecular interactions, thereby modulating key protein properties including enzymatic activity, stability, subcellular localization, and binding capacity. At the molecular level, these changes enable lactylation to regulate a broad spectrum of biological processes, such as gene expression, and programmed cell death. Consequently, lactylation is implicated in the pathogenesis of various diseases, including cancer, inflammatory disorders, and neurodegenerative diseases (Figure 6). cardiovascular diseases, cellular metabolism, transduction, signal In this review, we systematically summarized the reciprocal loop and highlighted how metabolic–lactylation feedback lactylation regulates metabolic enzyme properties, including catalytic activity, protein stability, and molecular interactions (Figure 5; Table 1). A recurring theme is that lactylation exerts bidirectional effects on enzyme function—either activating or inhibiting—depending on the specific enzyme, the modified residue, and the cellular context. Notably, the same enzyme can exhibit opposing functional outcomes when lactylated at different sites (Cheng et al., 2024; Mi et al., 2025; Gan et al., 2026; Xie et al., 2026). These observations underscore the importance of site-specific analysis in future studies. Previous analysis revealed that the number of lactylated proteins was far lower in normal cells than in tumor cells (Yang Y. H. et al., 2023), suggesting that aberrant lactylation may serve as a hallmark of metabolic rewiring in cancer—a notion consistent with the Warburg effect. This observation points to a bidirectional interplay between metabolic enzymes and lactylation. On one hand, metabolic lactate production and thereby shape the enzymes control lactylation lactylation exerts feedback two mechanisms. Directly, lactylation of metabolic enzymes per se alters their intrinsic properties, interactions. Indirectly, lactylation modulates the expression or activity of lactylation metabolic landscape. On the other hand, through regulation routes: histone including enzymes stability, activity, and two via enzymes. Mass epigenetically regulates the transcription of metabolic enzymes, while lactylation of other proteins affects the expression or activity of metabolic spectrometry-based identification across several tumor types has revealed eight metabolic enzymes that undergo lactylation in multiple cancers, six of which are closely linked to glucose metabolism. Beyond glucose metabolism, enzymes involved in lipid, nucleotide, and amino acid metabolism are also highly further emphasizing the pervasive interplay between this modification and cellular metabolism. lactylated, Despite these advances, several fundamental questions remain unanswered: • Beyond Activity and Stability: Multi-dimensional Regulation of

  generalfuture work
  Keywords: lactylation metabolic enzymes activity metabolism protein including stability enzyme molecular interactions properties expression diseases cellular
• The Lactate–Lactylation Axis as a Metabolic–Epigenetic Framework for Therapeutic Adaptation in Esophageal Squamous Cell Carcinoma (2026) · Cancers · doi

  The lactate–lactylation axis provides a framework for interpreting how metabolic stress translates into adaptive phenotypes in esophageal squamous cell carcinoma (ESCC). Current evidence supports a structured hierarchy rather than a single, uniform mechanism. Site-specific events have been functionally validated: PARP1 K654 lactylation enhances PARylation and DNA damage repair; STAT3 K631 and NUDT21 K23 lactylation alter vul- nerability to ferroptosis and cuproptosis; and HIF-1α K172 lactylation provides a preclinical link to hypoxia-associated immune evasion. Together, these studies link metabolic state to adaptive phenotypes through defined lactylation events. Broader lactylation-associated and metabolic-remodeling findings provide biologi- cal context, but do not themselves establish a causal role for a defined lactylation event. Inhibiting LDHA, MCT1, p300/CBP, or HIF-1α can alter lactate-related phenotypes, but https://doi.org/10.3390/cancers18182991 Cancers 2026, 18, 2991 20 of 27 none of these interventions is lactylation-specific. Their ESCC therapeutic windows and lactylation-dependent effects remain unresolved. Interpretation is further limited by uncer- tainty over whether writers and erasers distinguish L- from D-lactate-derived substrates and over acetylation–lactylation competition at shared lysine residues. Progress will require validated site-specific assays, spatial mapping of lactate sources, and stereochemical characterization of the modification machinery. Longitudinal, treatment- annotated cohorts should test whether lactylation signatures predict response indepen- dently of established clinical variables. Priority should be given to prospective valida- tion of ICI-associated mechanisms, including NIPAL1–H3K18la, and to tumor-selective approaches targeting validated lactylation events or their immediate effectors. The lactate– lactylation axis therefore represents a set of testable metabolic–epigenetic hypotheses for improving treatment stratification and precision intervention in ESCC. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cancers18182991/s1, Table S1. Verified quantitative and experi- mental parameters for representative lactate-lactylation studies in ESCC. Author Contributions: J.Y. conceived the review, performed literature analysis, and drafted the manuscript. Y.C. (Yiyuan Cui) and S.L. contributed to literature interpretation and manuscript revision. X.G., N.L., Y.G., Y.J., Y.C. (Yufan Chen), X.L., Y.Y., Z.W., and C.Z. contributed to literature collection, data curation, and manuscript review. L.F. supervised the study and critically revised the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: National Key R&D Program of China (2023YFC3503200, 2023YFC3503203). Institutional Review Board Statement: Not applicable. Data Availability Statement: No new data were created or analyzed in this study. Data sharing is not applicable to this article. Conflicts of Interest: The authors declare no conflict of interest.

  generalfuture work
  Keywords: lactylation lactate manuscript metabolic escc phenotypes specific events validated associated cancers review literature axis provides
• Progress in Lactate Metabolism and Its Regulation via Small Molecule Drugs (2024) · Molecules · cited 20× · doi

  In vivo, cells consume energy to decompose and synthesize molecules. Glucose, a key molecule for energy supply, is converted to pyruvate via the glycolytic process, and pyruvate produced by this process is often regarded as the core of the cellular energy metabolism. In healthy cells, pyruvate is transported into the mitochondria, where it undergoes oxidative phosphorylation to release energy. Conversely, under conditions of hypoxia or during high-intensity exercise, cells rely on glycolysis to produce lactate as a rapid source of energy [17,53]. Notably, the excessive accumulation of lactate has been closely associated with the pathogenesis and progression of various diseases, including liver disorders, tumors, and cardiovascular diseases [17,74,77,83]. Therefore, a compre- hensive understanding of lactate metabolism and its implications in disease processes is crucial for developing novel therapeutic strategies. lactate was once regarded as a simple by-product of glycolysis. With further research, its important physiological and patho- logical functions in organisms were gradually revealed. Histone lactylation modification, proposed in 2019, further amplified the importance of lactate [2], and its roles in the cellular energy supply [17], signal pathway regulation [35], epigenetic modification [2], and fat metabolism regulation [40] were gradually revealed. Lactate is not only an energy-provider to cells under hypoxic conditions; it is also a signaling molecule that can regulate the physi- ological functions of cells. When oxygen is in short supply, cells produce lactate through glycolysis as an alternative energy source to power the cells [53]. At the same time, lactate can also regulate cellular fat metabolic activity by affecting the synthesis of intracellular fatty acids [165]. Even more exciting is the new role of lactate in epigenetics. The discovery of histone lactylation modification has opened a new perspective for us to understand the role of lactate in the regulation of gene expression [2]. This modification may have similar functions to acetylation, methylation, and acetic acid modifications, and affect gene transcription and expression by changing the structure and stability of histones [27]. Although the study of gene expression changes after histone lactylation modification is still in its infancy, this field undoubtedly has great research potential and application value. Molecules 2024, 29, 5656 15 of 22 However, lactate accumulation is a problem that cannot be ignored in many diseases. Although lactate is often used as an important indicator for the diagnosis of certain dis- eases, studies have also found that supplementing blood vessels with lactate can alleviate heart disease [44–48]. In tumors, the accumulation of lactate not only provides energy for tumor cells but also participates in the regulation of immune responses and angio- genesis in the tumor microenvironment, promoting tumor growth and metastasis [54,55]. In l

  generalfuture work
  Keywords: lactate energy cells modification regulation supply pyruvate cellular metabolism glycolysis accumulation diseases functions histone lactylation
• Lactylation in sepsis-associated acute kidney injury: regulatory mechanisms and therapeutic prospects (2026) · Frontiers in Molecular Biosciences · doi

  Funding Lactate and lactylation form a biologically important but context-dependent regulatory network in SA-AKI. Direct SA- AKI studies support roles for H3K18la, Fis1 K20la, LDHB K156la, Ezrin K263la, HMGB1 lactylation, and ALDH2 K68la in mitochondrial injury, tubular cell death, endothelial barrier dysfunction, innate immune activation, and NET formation (An et al., 2023; Zhang et al., 2025; Huang et al., 2026; Qiao et al., 2024; Luo et al., 2026; Luo et al., 2025; Zhu et al., 2024; Wei et al., 2025; Huang et al., 2025; Li et al., 2025). However, lactate accumulation, lactic acidosis, transport, oxidation, metabolic routing, and lysine lactylation are distinct processes. A balanced model must recognize that lactate can be adaptive as a fuel, carbon source, redox-linked metabolite, and anti-inflammatory signal, while persistent or compartment-specific lactate availability may promote maladaptive lactylation. Several priorities follow. First, SA-AKI studies should map cell-type-specific lactylation landscapes and distinguish renal parenchymal events from systemic immune-cell and endothelial mechanisms. Second, direct lactylation assays should be paired with lactate flux, transporter expression, acid-base status, and pyruvate-routing measurements. Third, therapeutic studies should avoid global assumptions about LDHA inhibition or pyruvate oxidation and instead define the injury context, cell type, and intervention window. Finally, lactylation-based biomarkers require prospective validation before clinical use. With these safeguards, lactate-lactylation biology may provide a useful framework for understanding SA-AKI heterogeneity and for identifying more precise therapeutic targets.

  generalfuture work
  Keywords: lactylation lactate cell context direct injury endothelial immune huang oxidation routing specific type pyruvate therapeutic

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