Work

Phosphoglucomutase 5 suppresses gallbladder cancer progression by inhibiting lactate-driven STAT3 signaling

Year: 2026

Type: article

Abstract: • PGM5 is a tumor suppressor downregulated in gallbladder cancer. • PGM5 inhibits GBC progression by blocking lactate-driven STAT3. • PGM5 suppresses lactate production via LDHA downregulation. • PGM5 overexpression restrains tumor growth in a mouse model. Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract with limited therapeutic options. Phosphoglucomutase 5 (PGM5), a key enzyme in glucose metabolism, has been implicated as a tumor suppressor in several cancers, yet its role and mechanism in GBC remain unclear. Here, we demonstrate that PGM5 is significantly downregulated in GBC tissues, and its low expression correlates with poor prognosis. Using integrated bioinformatic analysis, we found that PGM5 loss is associated with enhanced glycolysis and activation of the STAT3 signaling pathway. Functionally, PGM5 overexpression significantly inhibited GBC cell proliferation, migration, and invasion, and promoted apoptosis, whereas PGM5 knockdown exerted the opposite effects. Mechanistically, PGM5 suppressed lactate production by downregulating lactate dehydrogenase A (LDHA), leading to decreased phosphorylation of STAT3. The anti-tumor effects of PGM5 were reversed by exogenous lactate supplementation, and the glycolytic inhibitor 2-DG abrogated the oncogenic phenotypes induced by PGM5 silencing. In a mouse xenograft model, PGM5 overexpression significantly restrained tumor growth, reduced LDHA and p-STAT3 levels, and decreased intratumoral lactate content. Our findings reveal that PGM5 acts as a tumor suppressor in GBC through disruption of the lactate-STAT3 signaling axis, highlighting its potential as a therapeutic target for metabolic intervention in GBC. Schematic illustration of the mechanism by which PGM5 inhibits gallbladder cancer progression through regulation of the “glycolysis–lactate–STAT3” axis. The graphical abstract was created with BioRender.com and is published with permission.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2026.102678