Phosphoglycerate dehydrogenase-mediated serine reprogramming aggravates macrophage hyperinflammation in murine Pseudomonas aeruginosa pneumonia.

Summary

In murine Pseudomonas aeruginosa pneumonia, PHGDH-driven serine synthesis fuels one‑carbon metabolism to amplify macrophage inflammation via H3K27me3–DUSP4 interaction and ERK1/2 activation. Genetic myeloid-specific PHGDH deletion, pharmacologic PHGDH inhibition, and dietary L‑serine restriction each reduced lung injury and bacterial load and improved survival.

Key Findings

• PHGDH inhibition (genetic and pharmacologic) suppressed macrophage hyperactivation and pro-inflammatory cytokine production.
• Myeloid-specific deletion of PHGDH improved survival, alleviated lung injury, and reduced bacterial load in murine P. aeruginosa pneumonia.
• Dietary L-serine restriction improved prognosis in infected mice.
• Mechanistically, PHGDH-driven L-serine synthesis augments one-carbon metabolism, strengthening H3K27me3–DUSP4 interaction and promoting ERK1/2 phosphorylation to amplify inflammation.

Clinical Implications

PHGDH and serine metabolism represent host-directed therapeutic targets to attenuate injurious inflammation in severe Pseudomonas pneumonia, potentially as adjuncts to antibiotics.

Limitations

• Preclinical murine and cell-based data; human translational validity remains to be established
• Potential off-target effects of pharmacologic inhibitors were not fully delineated
• Generalizability across bacterial pathogens and infection contexts not tested

Future Directions

Evaluate PHGDH/serine-pathway inhibitors and dietary modulation in translational models and early-phase trials; validate mechanisms in human macrophages and patient samples; assess synergy with antibiotics.