Epithelial FOXP3 Orchestrates O-Glycosylated IL6 Secretion to Drive Pancreatic Fibrocarcinogenesis

BACKGROUND & AIMS: Pancreatic fibrosis characterizes pancreatic ductal adenocarcinoma, driving therapeutic resistance and organ failure. However, the mechanisms initiating fibrosis during early preneoplastic stages remain unclear. We investigated the role of the transcription factor FOXP3, unexpectedly identified within the epithelial cells of precancerous lesions. METHODS: Using human tissues and genetically engineered mouse models, we analyzed FOXP3 expression in premalignant lesions. We used epithelial-specific FOXP3 knockout and knockin strategies to determine its functional impact on fibrogenesis and neoplasia progression. Mechanistic studies included chromatin immunoprecipitation, glycomic analyses, and signaling assays. The therapeutic potential of a fasting-mimicking diet was assessed in vivo. RESULTS: FOXP3 was consistently expressed in the epithelial compartment of human and murine precancerous pancreases. Epithelial-specific deletion of FOXP3 attenuated pancreatic fibrosis and delayed neoplasia, whereas its knockin induced spontaneous stromal activation and accelerated pancreatic intraepithelial neoplasia progression. Epithelial FOXP3 transactivated the glycosyltransferase GALNT1. GALNT1, in turn, mediated O-glycosylation of IL6 at threonine 165, essential for its rapid secretion. Secreted glycosylated IL6 engaged the gp130 receptor on pancreatic stellate cells, triggering a self-reinforcing MAPK/ERK signaling cascade that propagated stromal activation and established a feed-forward loop for fibrotic expansion. A threonine 165A mutation in IL6 abolished gp130 binding and pancreatic stellate cell activation. A fasting-mimicking diet suppressed the epithelial FOXP3/GALNT1 axis, inhibited IL6 glycosylation, and markedly ameliorated pancreatic fibrosis. CONCLUSIONS: Our study establishes epithelial-derived FOXP3 as a crucial regulator of early pancreatic fibrocarcinogenesis, driving a glycosylation-dependent amplification loop for IL6 signaling, orchestrating sustained stromal activation. This pathway represents a promising target for intercepting pancreatic fibrosis and carcinogenesis at its origin.