PRAS40-driven pro-inflammatory macrophage polarization is required for inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with unclear pathogenesis and limited therapeutic options. Macrophage dysfunction is central to IBD progression, yet how metabolic reprogramming governs macrophage function is poorly defined. Although the proline-rich Akt substrate of 40 kDa (PRAS40) is known to be important in colon cancer, its role in IBD is elusive. We found that PRAS40 mRNA expression was elevated in IBD patients, and its protein expression was similarly increased in IBD mouse models. Global PRAS40 deficiency alleviated IBD symptoms in mice, which was reversed by macrophage elimination. Consistently, myeloid-specific PRAS40 knockout mice recapitulated the protective phenotype in IBD mice. Metabolomic analysis revealed decreased amino acid levels in PRAS40-deficient BMDMs, with leucine and tryptophan identified as key drivers of macrophage polarization. Mechanistically, PRAS40 enhanced the phosphorylation of the transcription factor specificity protein 1 (SP1) to stabilize it through activating ERK and JNK signaling pathways. Upregulated SP1 augmented the transcription of solute carrier family 7 member 5 (SLC7A5), thereby boosting leucine and tryptophan uptake. This subsequently activated mTOR signaling, driving the pro-inflammatory polarization of macrophages. Collectively, PRAS40/SP1/SLC7A5 axis drives macrophage pro-inflammatory polarization by enhancing leucine and tryptophan uptake, thereby exacerbating IBD. These findings highlight the importance of amino acid reprogramming in macrophage polarization during IBD progression and propose targeting this axis as a potential therapeutic strategy for IBD.