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. 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.

代谢失调或许是炎症性肠病（IBD）的关键致病驱动因素，而代谢与免疫系统的交互调控现已成为重要研究热点。溃疡性结肠炎（UC）患者的肠黏膜呈现糖酵解增强但糖异生受抑的状态，然而此类代谢改变与黏膜损伤之间的机制关联仍尚未阐明。本研究确立了糖异生关键限速酶——磷酸烯醇式丙酮酸羧激酶1（Pck1）作为UC进展的核心调控因子。我们发现，UC患者及葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的结肠组织中，Pck1的表达水平显著下调。通过构建肠上皮细胞（IEC）特异性Pck1基因敲除小鼠模型，我们首次证实Pck1缺失会加剧肠道炎症反应。机制层面，Pck1缺失可诱导代谢重编程，上调磷脂酶A2 G6（Pla2g6）的表达，进而驱动肠上皮细胞内磷脂酰胆碱与磷脂酰乙醇胺的异常水解。对Pla2g6进行药物抑制可缓解Pck1缺失小鼠的结肠炎症状。上述研究结果将Pck1定位为UC潜在的早期诊断生物标志物，并提示靶向Pck1-Pla2g6代谢轴的治疗策略可为UC的临床管理提供全新思路。本研究对活动性UC患者（n=3）、缓解期UC患者（n=3）及健康对照者（n=3）的左侧结肠黏膜活检标本提取的总RNA进行了转录组测序（RNA-seq）。