The development of specific tools to detect, modulate

The gap

Evidence profile

Stated in the future work and conclusions sections 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.

  generalstated in future workevidence 5/5
  Keywords: llps lactylation cancer drug resistance mechanisms epigenetic protein manuscript synthesis anticancer strategies roles tumor develop
• Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances (2026) · Signal Transduction and Targeted Therapy · doi

  Research on lactate metabolism and lactate-derived lactylation, as core drivers of cancer initiation and progression, is gradually changing our traditional perception of lactate as a “metabolic 28 Lactate metabolism and lactylation in cancer: from pathogenesis to... Fang et al. waste product.” This review systematically examines the basic mechanisms of lactate metabolism, its abnormal manifestations in tumor cells, and the multiple roles of lactate in the TME. From the perspective of tumor initiation and progression, we reviewed the critical roles of lactate and lactylation modifications in transcriptional regulation, protein function modulation, immune evasion, and treatment resistance. The present review highlighted the role of lactate as an important mediator of signal transduction and epigenetic regulation, beyond its conventional function as an intermediate product of cellular metabolism. Mechanistically, tumor cells reprogram their metabolism to increase glycolysis, even under aerobic conditions (i.e., the Warburg effect), significantly increasing lactate production. Subsequently, glutamine metabolism becomes an important source of lactate, supporting the energy and biosynthetic precursor demands of rapid tumor proliferation while promoting immune suppression, angiogenesis, and metastasis by acidifying the TME. Additionally, the lactate shuttle mechanism facilitates metabolic symbiosis between different regions of tumor cells. Lactylation, a novel form of posttranslational protein modification, expands the connection between metabolic products and epigenetic regulation. The “writers” (such as p300, GCN5, and KAT8), “erasers” (such as HDACs and the SIRT family), and “readers” (such as Brg1 and DPF2) of lactylation constitute a highly dynamic regulatory system. These modifications are present on histones, regulating the open state and transcriptional activity of key genes. They also widely affect nonhistone proteins, influencing biological the cell cycle, and drug processes, resistance. The differences such as L-lactylation and D-lactylation, and their source pathways (enzymatic or nonenzymatic) also provide new insights into tumor molecular heterogeneity and therapeutic target development. in lactylation isomers, including DNA repair, Notably, lactate and lactylation exhibit significant dynamics and duality across different stages of cancer. During tumor initiation, lactate accelerates carcinogenesis by inducing DNA mutations, impairing tumor suppressor gene function (such as p53 lactylation), and remodeling the immune microenvironment. During it supports malignant clone tumor expansion and invasion, selection and expansion by acidifying the microenvironment and driving immune tolerance. Moreover, during cancer treatment, lactylation confers drug resistance by enhancing DNA repair and inhibiting immune responses.

  generalstated in future workevidence 5/5
  Keywords: lactate lactylation tumor metabolism immune cancer initiation metabolic cells modi regulation function resistance progression product
• 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.

  generalstated in conclusionsevidence 5/5
  Keywords: specific future focus development tools detect modulate visualize lactylation dynamics vivo full repertoire lactylated proteins

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