The mechanism of gluconeogenic enzyme Pck1 in ulcerative colitis through regulation of Pla2g6-mediated lipid metabolism II
Metabolic dysregulation may serve as a pivotal driver of inflammatory bowel disease (IBD), with the crosstalk between metabolism and the immune system emerging as a critical research focus. Ulcerative colitis (UC) patients exhibit enhanced glycolysis but suppressed gluconeogenesis in the intestinal mucosa, yet the mechanistic links between these metabolic alterations and mucosal injury remain poorly defined. This study establishes phosphoenolpyruvate carboxykinase 1 (Pck1), a key rate-limiting enzyme in gluconeogenesis, as a central regulator of UC progression. We found Pck1 expression was significantly downregulated in colon tissues of UC patients and mice with DSS-induced colitis. Utilizing an intestinal epithelial cell (IEC)-specific Pck1 knockout mouse model, we demonstrated for the first time that Pck1 deficiency exacerbates intestinal inflammation. Mechanistically, Pck1 depletion induces metabolic reprogramming that upregulates Pla2g6 expression, driving abnormal hydrolysis of phosphatidylcholine and phosphatidylethanolamine in IECs. Pharmacological inhibition of Pla2g6 ameliorated colitis in Pck1-deficient mice. These findings position Pck1 as a potential early diagnostic biomarker for UC and suggest that therapeutic targeting of the Pck1-Pla2g6 metabolic axis may yield novel strategies for UC management. Overall design: The RNA extracted from left-sided colonic mucosal biopsy specimens of active UC patients (n=3), remission UC patients (n=3), and healthy controls (n=3) was subjected to RNA-seq.