PGD suppresses lymph node metastasis in esophageal squamous cell carcinoma by inhibiting the JAK1–STAT3 signaling

ABSTRACT: Lymph node (LN) metastasis is a distinct pathway of cancer dissemination and represents the predominant metastatic route in esophageal squamous cell carcinoma (ESCC). However, effective therapeutic targets and biomarkers specifically addressing LN metastasis are clinically lacking, due to an incomplete understanding of its underlying molecular mechanisms. Here, we identified phosphogluconate dehydrogenase (PGD), a key metabolic enzyme in the pentose phosphate pathway, as a previously unrecognized suppressor of LN metastasis in ESCC. Integrative proteomic analysis revealed significant downregulation of PGD in ESCC, particularly in LN-metastatic tumors. Clinically, low PGD expression correlated with poor patient survival. Functional assays demonstrated that PGD overexpression markedly suppressed ESCC cell migration in vitro and inhibited LN metastasis in vivo, whereas PGD depletion promoted opposite effects. Mechanistically, co-immunoprecipitation and mass spectrometry identified Janus kinase 1 (JAK1) as a direct interacting partner of PGD. We found that PGD disrupts the JAK1–STAT3 interaction, leading to attenuated STAT3 phosphorylation and subsequent suppression of matrix metalloproteinase-13 (MMP13) transcription, a critical mediator of extracellular matrix remodeling and metastasis. The pro-metastatic phenotype induced by PGD loss was effectively reversed by pharmacological inhibition of STAT3, affirming the functional significance of the PGD–JAK1–STAT3 axis. Consistent with these findings, PGD expression was inversely correlated with p-STAT3 and MMP13 levels in clinical specimens. Collectively, our findings uncover a non-metabolic role of PGD in inhibiting lymphatic metastasis through the JAK1–STAT3–MMP13 signaling pathway, and highlight PGD as a potential prognostic marker and therapeutic target for ESCC with LN metastasis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ning Ma  

PROVIDER: PXD079102 | iProX | Sat May 30 00:00:00 BST 2026

REPOSITORIES: iProX