The development of specific tools to detect, modulate and visualize lactylation dynamics in vivo

The gap

Evidence profile

Sourced from the future work and conclusions of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• Liquid-liquid phase separation in cancer: oncogenic roles, therapeutic potential, and epigenetic regulation (2026) · Molecular Biology Reports · doi

  LLPS is a common cellular behavior that regulates DNA synthesis, RNA synthesis, and processing, and signal trans- duction [1]. In various cancer types, LLPS can promote the proliferation, metastasis, and drug resistance of cancer cells by affecting BRD4 [6–9] and p53 [8, 9]. LLPS is regulated by several mechanisms, especially epigenetic modification. Therefore, targeting LLPS may facilitate the development of effective and promising anticancer strategies. Nowadays, increasingly more studies have revealed the critical regula- tory roles of LLPS during tumor progression, but multiple problems remain to be solved. First, we know little about the exact and detailed mechanisms of LLPS-mediated tumorigenesis. Second, there is still a poor understanding of more epigenetic mechanisms underlying protein modifica- tion-caused LLPS in cancer. Third, further investigation is needed to develop LLPS-based anticancer methods. Against this background, protein lactylation has emerged as a newly identified and important epigenetic post-translational modi- fication [79]. However, its biological link with LLPS in can- cer remains unclear. Nevertheless, emerging studies suggest that lactylation may affect downstream gene transcription and cancer-related phenotypes in specific contexts [80]. Separately, limited evidence has hinted at a possible con- nection between lactylation-associated changes and LLPS in tumors [81]. Overall, exploring the regulatory connection between protein lactylation and phase separation in can- cer is quite important. Additionally, given that lactylation is associated with tumor drug resistance, these findings may provide a rationale for future therapeutic exploration aimed at overcoming drug resistance, for example through glycolysis inhibition or modulation of histone lactylation, such as H3K18 lactylation [82, 83]. In summary, unraveling the oncogenic roles, therapeutic potentials, and epigenetic Molecular Biology Reports (2026) 53:663 1 3 663 Page 10 of 12 regulatory mechanisms of liquid-liquid phase separation will help develop novel strategies for cancer control and to overcome drug resistance. Acknowledgements We gratefully acknowledge the use of BioRender (https://www.biorender.com/) for the creation of scientific illustrations in this study. Author contributions ZZH wrote the manuscript. ZZH and LT pre- pared the figures. SZZ revised the manuscript. All authors reviewed the manuscript. Funding This study was funded by the National Natural Science Foundation of China (No. 82160585), Joint Medical Program of Kun- ming University of Science and Technology (KUST-KH2022001Z and KUST-PE2022002Z), and the innovation team of oxidative stress and defense of Yunnan Province (202305AS350011). Data availability No datasets were generated or analysed during the current study.

  generalfuture work
  Keywords: llps lactylation cancer drug resistance mechanisms epigenetic protein manuscript synthesis anticancer strategies roles tumor develop
• Metabolic Signaling Meets Epigenetic Regulation: How Protein Lactylation Remodels the Tumor Immune Microenvironment in Gastric Cancer (2026) · Current Issues in Molecular Biology · doi

  Despite groundbreaking insights, lactylation research in GC remains nascent. To unlock its full biological and therapeutic potential, future efforts must focus on three interconnected frontiers: panoramic mapping, reader elucidation, and clinical translation. 5.1. Mapping the Panoramic and Dynamic Landscape of Lactylation in GC A comprehensive understanding requires moving beyond bulk analyses to chart the het- erogeneous and dynamic distribution of lactylation across the tumor ecosystem. Leveraging emerging technologies—single-cell lactylomics (integrating scRNA-seq with sensitive mass spectrometry), spatial transcriptomics/proteomics, and artificial intelligence—will be pivotal. Key research goals include: resolving cellular heterogeneity by determining the specific distribution and function of lactylation across malignant subclones, immune cells (TAMs, T cells), and cancer-associated fibroblasts (CAFs); mapping spatiotemporal dynamics by tracing lactylation marks during tumor initiation, progression, therapy response, and resistance development; and investigating subtype specificity by comparing lactylation https://doi.org/10.3390/cimb48060595 Curr. Issues Mol. Biol. 2026, 48, 595 21 of 29 profiles across GC molecular subtypes (e.g., EBV-positive, MSI-H, genomically stable) to identify subtype-specific vulnerabilities and biomarkers. These efforts will provide an unprecedented systems-level view of GC heterogeneity, drug resistance mechanisms, and novel therapeutic targets [37]. 5.2. Deciphering the “Readers” and Precise Regulatory Network of Lactylation While knowledge of lactylation “writers” (AARS1, p300) and “erasers” (SIRT1, HDACs) is increasing, identifying the specific “reader” proteins that recognize lactyla- tion marks and mediate downstream effects remains a critical gap. Proteomic screening (e.g., with lactylated peptide baits) and structural biology can help validate reader domains (e.g., bromodomains, YEATS domains) that bind distinct lactylation sites such as H3K18la, with initial studies like TRIM33’s bromodomain binding to H3K18la paving the way [81]. Equally important is deconstructing how writers, erasers, and readers form a dynamic reg- ulatory circuit and crosstalk with other PTMs (e.g., acetylation, methylation). Deciphering readers is essential for understanding lactylation-driven gene regulation and provides a theoretical foundation for drugs that interfere with signal readout. Despite progress in identifying lactylation readers, major challenges remain. Cur- rently, the number of validated readers in GC is limited, and the roles of many potential recognition proteins (e.g., those containing YEATS domains) remain unexplored [126]. Reader functions are highly context-dependent, and the same protein may exert opposing effects in different GC subtypes or cellular environments. A critical bottleneck is the lack of highly selective probes or tools that can distinguish lactylation from structurally sim- ilar modifica

  generalfuture work
  Keywords: lactylation readers reader mapping dynamic across specific domains despite remains therapeutic potential efforts panoramic understanding
• Understanding the epigenetic regulation of lactylation and aberrant lactate metabolism in cancer: From mechanisms to therapeutic strategies (Review) (2026) · International Journal of Oncology · doi

  Future studies should focus on the development of specific tools to detect, modulate and visualize lactylation dynamics in vivo. The full repertoire of lactylated proteins, their site‑specific regulatory mechanisms, and their functional implications in different cancer types and stages remain to be fully elucidated. Additionally, there is a lack of standardized models to evaluate the synergistic effects of combining lactate metabo‑ lism inhibitors with epigenetic drugs.

  generalconclusions
  Keywords: specific future focus development tools detect modulate visualize lactylation dynamics vivo full repertoire lactylated proteins

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