The research, led by Xinyi Liu and Wenqian Du, who contributed equally as co-first authors, with Yan Zheng serving as corresponding author, set out to answer a deceptively simple question: what drives the metabolic reprogramming that characterizes cutaneous squamous cell carcinoma? Cancer cells famously prefer to burn glucose through glycolysis even when oxygen is plentiful, a phenomenon known as the Warburg effect, but the upstream signals that lock tumor cells into this energy-hungry mode are incompletely mapped in skin cancer. The team suspected that SLC25A1 might be involved because the protein occupies a strategically important position in cellular metabolism. By exporting citrate from the mitochondrial matrix into the cytosol, SLC25A1 supplies the raw material for lipid synthesis and, critically, for the production of acetyl-coenzyme A, the universal acetyl-group donor that fuels chemical tagging of proteins throughout the cell.

To test this hypothesis, the researchers first examined SLC25A1 expression in clinical tissue samples and in cell lines derived from cutaneous squamous cell carcinoma. Using immunohistochemistry to visualize protein localization in tissue sections, reverse transcription quantitative polymerase chain reaction to measure messenger RNA levels, and Western blotting to quantify protein abundance, they found that SLC25A1 was significantly upregulated in tumor tissue compared with healthy counterparts. This consistent overexpression across multiple measurement modalities suggested that the transporter was not an incidental passenger but an active participant in the disease process, prompting the team to manipulate its levels experimentally and observe the consequences for cancer cell behavior.

The functional experiments produced striking results. When the researchers knocked down SLC25A1 expression using molecular tools, the cancer cells lost several of their most dangerous properties: proliferation slowed, apoptosis, the programmed self-destruction that healthy cells undergo when damaged, increased, and the cells became markedly less capable of migration and invasion, the processes that allow tumors to spread into surrounding tissue. Conversely, forcing overexpression of SLC25A1 enhanced all of these malignant behaviors. These gain-of-function and loss-of-function experiments, performed in complementary directions, established a causal relationship rather than a mere correlation, satisfying one of the most demanding standards in cancer biology.

The mechanistic heart of the study lies in what the researchers discovered when they probed how SLC25A1 exerts its influence. RNA sequencing of cells with altered SLC25A1 levels, combined with metabolic assays measuring glycolytic activity, revealed that the transporter boosts glycolysis by upregulating a gene called ALDOC, which encodes aldolase C, a glycolytic enzyme that cleaves fructose-1,6-bisphosphate into the triose phosphates that feed the lower half of the glycolytic pathway. But the truly novel finding concerned how ALDOC was activated. Using chromatin immunoprecipitation followed by quantitative polymerase chain reaction, a technique that allows researchers to determine which chemical marks sit on specific stretches of DNA, the team showed that SLC25A1 increased pan-histone H3 acetylation at the ALDOC promoter region.

This mechanism represents an elegant metabolic-epigenetic circuit. Histones are the spools around which DNA winds, and when acetyl groups are added to histone tails, the chromatin relaxes, exposing genes to the transcriptional machinery and switching them on. Because acetyl-coenzyme A is the substrate for histone acetyltransferases, the availability of citrate exported by SLC25A1 can directly govern how much acetylation occurs across the genome. In cutaneous squamous cell carcinoma cells, elevated SLC25A1 appears to flood the nucleus with acetyl-coenzyme A, opening up the ALDOC promoter, increasing aldolase C production, and thereby accelerating glycolytic flux. The tumor cell essentially uses its own mitochondrial exporter to write epigenetic instructions that command more sugar burning, creating a self-reinforcing loop that sustains rapid growth.

The researchers then confirmed the importance of this circuit through rescue experiments. When SLC25A1 was knocked down, glycolytic activity and tumor growth declined, but re-introducing ALDOC through overexpression partially restored these malignant phenotypes. This partial rescue is significant because it demonstrates that ALDOC is a functional downstream mediator of SLC25A1’s effects, while also hinting that the citrate transporter may influence additional targets beyond this single glycolytic enzyme. Such layered regulation is typical of metabolic reprogramming in cancer, where multiple pathways converge to reinforce the transformed state, and it underscores why upstream nodes like SLC25A1 make attractive therapeutic targets.

Crucially, the team extended their findings from cell culture into living organisms. Using the classic DMBA/TPA chemical carcinogenesis model, in which mice are treated with a mutagen followed by a tumor promoter to induce cutaneous squamous cell carcinoma, the researchers evaluated whether blocking SLC25A1 pharmacologically could suppress tumor development. They employed CTPI-2, a selective inhibitor of the SLC25A1 citrate transporter, and found that treatment suppressed tumor progression and altered metabolic profiles in vivo. This pharmacological validation is a critical step toward clinical relevance, because it demonstrates that the mechanism discovered in petri dishes can be exploited with drug-like molecules in a whole-animal context, where issues of tissue penetration, metabolism, and systemic physiology come into play.

The implications of the study extend beyond skin cancer. SLC25A1 has been implicated in tumor progression in other malignancies, and the coupling of citrate export to histone acetylation provides a general framework for understanding how metabolic state shapes the epigenetic landscape. For patients with cutaneous squamous cell carcinoma, most of whom are cured by surgery but a subset of whom face aggressive, metastatic disease, the identification of a druggable metabolic-epigenetic axis offers hope for new options. The work was supported by the National Natural Science Foundation of China and funds from Shaanxi Province, and it was conducted under ethical approval from the Biomedical Ethics Committee of the Health Science Center of Xi’an Jiaotong University, with all animal experiments following institutional guidelines. While clinical translation will require further studies of CTPI-2 and related compounds, including safety profiling and combination strategies with existing therapies, the study provides a compelling proof of concept that starving a skin tumor of its epigenetic fuel supply can slow its advance. As metabolic oncology matures from observation to intervention, transporters like SLC25A1 are emerging not as passive conduits but as command centers, and this research adds an important chapter to that evolving story.

Subject of Research: The role of the mitochondrial citrate transporter SLC25A1 in regulating glycolysis and histone acetylation during cutaneous squamous cell carcinoma progression.

Article Title: SLC25A1 regulates glycolysis via ALDOC global histone H3 acetylation to promote cutaneous squamous cell carcinoma development

Article References: Liu, X., Du, W., Wang, J., Yin, T., He, K., Zhang, Z., Liu, M., Gan, X., Cheng, B., Luo, R., & Zheng, Y. (2026). SLC25A1 regulates glycolysis via ALDOC global histone H3 acetylation to promote cutaneous squamous cell carcinoma development. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08857-w

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08857-w

Keywords: SLC25A1, cutaneous squamous cell carcinoma, glycolysis, ALDOC, histone H3 acetylation, cancer metabolism, CTPI-2, mitochondrial citrate transporter, epigenetics, skin cancer, Warburg effect, tumor progression