From the nucleus to the cell membrane: How does protein lactylation shape cancer?

Cancer cells often produce large amounts of lactate as they break down glucose. Once regarded mainly as a metabolic waste product, lactate is now known to play a role in regulating cellular functions. One way it does this is through protein lysine lactylation, a chemical modification that can alter a protein's activity, stability, or interactions. Its effects, however, may depend on the modified protein and where it is located within the cell.

In a review published on October 14, 2026, in SCIENCE CHINA Life Sciences, researchers from Capital Medical University and Tongji University review protein lactylation from this spatial perspective. Their article, "From nuclear discovery to organelle-wide regulation: protein lactylation in cancer," brings together findings from studies of lactylation in the nucleus, cytoplasm, mitochondria, cell membrane, and endomembrane system. The review explores how cellular location may influence the biological effects of lactylation in cancer.

The review also examines the molecular machinery that controls lactylation. Writers, including p300/CBP and AARS1/2, catalyze the addition of lactyl groups to proteins, while erasers, such as certain HDACs and sirtuins, remove them. Readers recognize specific lactylation marks, although only a few have been experimentally validated. These regulators differ in their subcellular localization and substrate preferences, which may help explain the varied effects of lactylation.

The discovery of histone lactylation in 2019 first drew widespread attention to this modification. Histones are proteins that help package DNA, and their lactylation can influence gene expression, often by promoting transcription. Subsequent studies have identified lactylation on other nuclear proteins involved in DNA repair, transcriptional regulation, and RNA processing.

Lactylation is not confined to the nucleus. In the cytoplasm, it can affect metabolic enzyme activity, protein stability, and cellular signaling. In mitochondria, lactylation has been linked to changes in metabolism, redox balance, and cellular responses to stress. At the cell membrane, lactylation of proteins involved in signaling and immune recognition may influence how tumor cells interact with their surroundings. Studies have also begun to uncover roles for lactylation in the endomembrane system, including vesicle trafficking, protein transport, and autophagy.

Specific lactylation events have been linked to tumor growth, immune evasion, and resistance to treatment. Their effects, however, are not always the same. The biological outcome depends on the modified protein, the specific site, and the cellular context. Understanding these differences will be important when considering lactylation as a potential therapeutic target.

Several questions remain unanswered. The enzymes responsible for many lactylation events are still unknown, and conventional proteomic methods often analyze whole-cell samples, making it difficult to distinguish modifications occurring in different cellular compartments. The authors emphasize the need for more precise approaches, including subcellular proteomics and site-specific validation, to better understand how lactylation is regulated and what it does.

By extending the focus beyond the nucleus, the review brings together evidence of lactylation across different cellular compartments. A clearer understanding of these spatial differences may help researchers identify more selective targets for future cancer therapies.