Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6

Gong, R.; Ren, M.; Wang, J.; Zhang, W.; Ping, S.; Ke, L.; Qian, Y.; Ma, L.; Gao, C.; Zhao, C.; Fu, S.; Xue, J.; Sun, H.; Chen, J.; Zhang, S.; Liu, M.; Zhao, T.; Saluja, A.; Yang, Z.; Ren, H.

doi:10.1101/2025.11.19.689208

bioRxiv · 10.1101/2025.11.19.689208

Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6

Gong, R.·Ren, M.·Wang, J.·Zhang, W.·Ping, S.·Ke, L.·Qian, Y.·Ma, L.·Gao, C.·Zhao, C.·Fu, S.·Xue, J.·Sun, H.·Chen, J.·Zhang, S.·Liu, M.·Zhao, T.·Saluja, A.·Yang, Z.·Ren, H.

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Abstract

BACKGROUND & AIMSThe transcription factor FOXP3, known for specifying regulatory T cell fate, is unexpectedly expressed in the epithelium of precancerous pancreatic lesions. Here we investigate its non-immune role in initiating pancreatic fibrosis, a process driving therapeutic resistance and organ failure in pancreatic ductal adenocarcinoma (PDAC) with unknown origins in early neoplasia. METHODSUsing human tissues and genetically engineered mouse models, we analysed FOXP3 expression in premalignant lesions. We employed epithelial-specific FOXP3 knockout and knock-in strategies to determine its functional impact on fibrogenesis and neoplasia progression. Mechanistic studies included chromatin immunoprecipitation, glycomic analyses, and signalling assays. RESULTSFOXP3 was consistently expressed in the epithelial compartment of human and murine precancerous pancreas. Epithelial-specific deletion of FOXP3 attenuated pancreatic fibrosis and delayed neoplasia, whereas its knock-in induced spontaneous stromal activation and accelerated PanIN progression. Mechanistically, epithelial FOXP3 directly transactivated the glycosyltransferase GALNT1. GALNT1, in turn, mediated O-glycosylation of interleukin (IL)-6, which was essential for its rapid secretion. CONCLUSIONSOur study establishes epithelial-derived FOXP3 as a master regulator of early pancreatic fibrocarcinogenesis. It drives a glycosylation-dependent amplification loop for IL-6 signalling, orchestrating sustained stromal activation. This pathway represents a promising target for intercepting pancreatic fibrosis and carcinogenesis at its origin.

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Gong, R., Ren, M., Wang, J., Zhang, W., Ping, S., Ke, L., Qian, Y., Ma, L., Gao, C., Zhao, C., Fu, S., Xue, J., Sun, H., Chen, J., Zhang, S., Liu, M., Zhao, T., Saluja, A., Yang, Z., Ren, H.. 2025-11-19. Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6. https://doi.org/10.1101/2025.11.19.689208

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