Downregulation of NFIA facilitates glycolysis, histone lactylation, and activation of the FN1-integrin α5β1 pathway in pancreatic cancer

Abstract

Pancreatic cancer (PC) is a lethal malignancy with limited therapeutic options, characterized by tumor suppressor loss and metabolic-stromal crosstalk. This study aimed to introduce nuclear factor I A (NFIA) as a key tumor suppressor whose downregulation in PC was correlated with advanced tumor stages and poor prognosis. Functionally, NFIA overexpression suppressed PC cell proliferation, migration, and invasion, whereas NFIA silencing exacerbated these malignant phenotypes. Mechanistically, NFIA directly repressed the transcription of the glycolytic enzyme PKM, thereby attenuating glucose uptake and lactate production. Lactate generated from NFIA deficiency-induced glycolysis promoted histone lactylation, which epigenetically upregulated fibronectin 1 (FN1) expression in both cancer cells and cancer-associated fibroblasts. Elevated FN1 activated the integrin α5β1-FAK-PI3K-Akt signaling axis, thereby fostering invasive and metastatic behavior. Furthermore, NFIA transcriptionally suppressed FN1 expression, establishing a dual regulatory mechanism that bridged metabolic reprogramming and extracellular matrix remodeling. Collectively, our study indicated NFIA as a key tumor suppressor of PC progression, orchestrating the crosstalk between glycolysis inhibition and FN1-integrin pathway inactivation. These findings position NFIA restoration as a therapeutic strategy to disrupt metabolic-stromal synergy in aggressive PC, offering insights into the epigenetic-metabolic interplay underlying tumor microenvironment evolution.

Keywords: FN1; Glycolysis; Histone lactylation; NFIA; Pancreatic cancer.