Phosphoglycerate dehydrogenase interacts with and inhibits the protein kinase TAK1 to mitigate septic shock

Dysregulation of macrophage-mediated inflammatory responses is central to sepsis pathogenesis, making its modulation crucial for reducing organ damage and mortality. This study reveals that the key serine synthesis enzyme phosphoglycerate dehydrogenase (PHGDH), known for regulating tumor and immune cell functions, is significantly downregulated in mouse macrophages following LPS stimulation, as well as in patients with systemic inflammatory response syndrome (SIRS) or sepsis. PHGDH knockdown enhances inflammatory responses to LPS and E. coli in vitro, while myeloid PHGDH knockout exacerbates inflammation and organ damage in septic mouse models. In contrast, deficiency in serine and its derivative glycine inhibits LPS-induced macrophage inflammation both in vitro and in vivo. Mechanistically, PHGDH interacts with TAK1, inhibiting TAK1 binding to TAB1, thereby suppressing the TAK1-NF-κB/MAPK signaling pathway. Furthermore, AAV-mediated PHGDH overexpression in lung macrophages reduces sepsis-related inflammation and damage, highlighting PHGDH's non-metabolic role in regulating macrophage-mediated inflammation and suggesting new therapeutic strategies for sepsis treatment.