Abrogation of serine metabolism exacerbates intestinal epithelial inflammation via C/EBPβ-NF-κB pathway

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation and metabolic dysregulation in the intestinal epithelium. Serine, a non-essential amino acid synthesized via the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH), maintains celular redox balance. Serine metabolism is upregulated in cancer and immune cells, supporting survival and growth. Our previous study showed ER stress mediated rewiring of serine metabolism was a key molecular feature in IBD. However, the mechanism of how PHGDH-related serine metabolism influences the IBD process remains unclear. Clinical analysis of PHGDH was assessed in the public database of IBD cohorts, correlating PHGDH expression with endoscopic or clinical disease activity. To explore the molecular regulation of de novo serine synthesis via PHGDH, we used murine intestinal epithelial cells (Mode-K cells) and murine intestinal organoids. WB and IHC were performed to analyze in vitro ER stress and PHGDH expression in the DSS colitis model. Mode-K cells were subjected to serine starvation and co-treated with LPS. Proinflammatory cytokines were evaluated by qPCR and ELISA. Metabolic supplements formate and hypoxanthine were tested to mitigate the overactivation of inflammation. Total starvation was assessed by using serine deprivation medium and the PHGDH inhibitor BI-4916. RNA sequencing and proteomic analyses were performed to investigate molecular mechanisms. Clinicaly, we observed upregulated PHGDH expression in IBD patients, showing a strong association between serine metabolism and IBD severity. Using the DSS induced colitis model, we showed elevated ER stress and serine synthesis under inflammation. When the serine pathway was completely blocked, we observed a dramatica ly enhanced inflammatory signature upon LPS treatment. Total starvation led to impaired mitochondrial function as assessed by the Seahorse assay. Combining RNAseq and proteomic analysis, we identified C/EBPβ as the critical regulator in mediating cellular inflammation under total serine starvation via the NF-κB pathway. In this study, we revealed that disruption of serine metabolism accelerated intestinal inflammation via the C/EBPβ NF-κB axis, which provided new insights into the pathophysiology of IBD.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Christian-Albrechts-Universität zu Kiel

Year

2026

Author dc:creator

• Yang, Guang

Contributors dc:contributor

• Aden, Konrad
• Hammer, Quirin

• IBD
• PHGDH
• Serine metabolism

Repository record source_url

https://macau.uni-kiel.de/receive/macau_mods_00008349

OAI identifier oai:identifier

oai:macau.uni-kiel.de:macau_mods_00008349