Blood-vessel cell protein CLEC3B may slow liver cancer by curbing tumor lactylation and autophagy

The patients in this study were all on an operating table in Tianjin when the samples were taken. Between January 1 and December 31, 2025, surgeons in the Department of General Surgery at Tianjin Medical University General Hospital removed liver tumors from 42 people with hepatocellular carcinoma. They also took adjacent non-tumorous tissue from more than 2 centimeters beyond the tumor margin, plus preoperative blood. None of the 42 had received chemotherapy, radiotherapy, or targeted therapy beforehand. The tissue was snap-frozen in liquid nitrogen and stored at minus 80 degrees Celsius. A comparison group of 20 patients who had surgery for liver trauma supplied blood for measuring circulating levels of the protein at the center of the work.

That protein is CLEC3B, also called tetranectin, a secreted, calcium-binding member of the C-type lectin family. The paper, published in PLOS Computational Biology, argues that CLEC3B is released by liver sinusoidal endothelial cells, the fenestrated cells lining the liver's blood channels. These are the most abundant non-parenchymal cells in the liver, and among the first to respond to liver injury. The authors report that CLEC3B is significantly reduced in liver cancer, and that tumor cells exposed to it grow more slowly.

The backdrop is a hard clinical picture. Liver cancer ranks sixth in incidence among cancers and is the third leading cause of cancer death worldwide. Hepatocellular carcinoma makes up more than 80 percent of cases. Advanced disease still carries a poor prognosis because of recurrence, metastasis, and resistance to therapy. The authors say that which molecules endothelial cells secrete to restrain or feed these tumors has been largely unexplored.

The team came to CLEC3B through two processes that cancer biologists increasingly study together. One is lactylation, a chemical modification of proteins driven by lactate, which tumors produce in large amounts through the Warburg effect. The other is autophagy, the cell's recycling system, which can either suppress tumor initiation or help cancer cells survive stress. Earlier work cited in the paper links the two: lactylation of TFEB boosts autophagic and lysosomal activity, lactylation of FLCN at lysine 523 promotes TFEB-driven autophagy, and in pancreatic cancer, lactylation of FOXO3 sustains autophagy. What connects them in liver cancer, and whether a secreted factor from supporting cells is involved, the authors describe as unknown.

To search for one, they built a gene signature tied to lactylation and autophagy from public cohorts, TCGA and ICGC, and used it to sort liver cancer patients into molecular subtypes with different survival. CLEC3B emerged as a core component of that prognostic model. Prior studies had already reported it downregulated in several cancers and linked to poor survival in liver cancer, and one found it reduced in liver cancer exosomes, where it suppressed metastasis and angiogenesis through AMPK and VEGF signaling. The new study adds single-cell RNA sequencing data from normal mouse liver, normal human liver, and human liver cancer tissue, along with laboratory experiments, to place CLEC3B's source in the liver's endothelial cells.

Inside tumor cells, the authors report, CLEC3B dampens both lactylation and autophagy at once. Their data suggest the drop in lactylation comes first and leads to the inhibition of autophagy. In their framing, the protein is a tumor-suppressive signal from blood vessels that disrupts a metabolic and self-recycling axis within cancer cells.

The work has clear limits. It rests on public datasets, experiments, and 42 patients from a single hospital. The proposal that restoring CLEC3B signaling, or targeting the pathways it controls, could become a treatment has not been tested clinically. The next steps would be showing that the mechanism holds in living tumors and in larger, independent patient groups.