ERO1L induces macrophage infiltration to potentiate Kras^G12D and inflammation-induced pancreatic tumorigenesis via oxidative protein folding of CCL2

Pancreatitis is a significant risk factor for pancreatic cancer, with Kras mutations being the most common in this malignancy. Inflammation accelerates tumorigenesis driven by Kras mutations. However, the interactions between inflammation and Kras mutation in the context of pancreatic tumorigenesis remain unclear. In this study, we discovered that under pancreatitis conditions, the endoplasmic reticulum stress-related pathways are downregulated in Kras mutant mice compared to wild-type mice, while endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is abnormally upregulated. Kras mutation downregulates the ER-associated E3 ubiquitin ligase HRD1, resulting in reduced ubiquitination and degradation of HIF1α, which transcriptionally induces the expression of ERO1L. Inhibition of ERO1L activity or pancreas-specific knockout of the Ero1l gene can delay the progression of pancreatic carcinogenesis. Mechanistically, ERO1L enhances the protein expression of the chemokine CCL2 through its role in oxidative folding, thereby promoting the recruitment of macrophages. Thus, this study reveals that Kras mutation upregulates ERO1L to promote inflammation and pancreatic tumorigenesis, providing new insights and potential targets for the treatment of pancreatic cancer.