Lipocalin-type prostaglandin D₂ synthase (L-PGDS) deficiency disrupts heme catabolism and iron homeostasis in mice.

Efficient recycling of red blood cells (RBCs) requires not only heme cleavage but also stabilization of reactive intermediates generated during iron liberation. Lipocalin-type Prostaglandin D₂ Synthase (L-PGDS, β-trace protein), best known for prostaglandin synthesis, possesses structural and biochemical features consistent with a buffering role in heme catabolism. Here, we show that L-PGDS knockout mice exhibit elevated plasma, increased total splenic iron, reduced total hepatic iron, decreased plasma free heme/hemin, and modest RBC enlargement, consistent with disrupted iron release. Transcript-protein mismatches in key iron regulators, including NRF2 and FPN, further suggest redox imbalance and impaired iron sensing. Despite normal Hmox1 expression, these mice display widespread evidence of inefficient porphyrin clearance. Combined with prior findings that L-PGDS binds ferric biliverdin and is upregulated during heme overload, our results support a model in which L-PGDS buffers porphyrin intermediates to facilitate their safe processing and clearance. This study identifies L-PGDS as a putative auxiliary factor in heme catabolism, with implications for iron recycling, erythropoiesis, and systemic iron homeostasis. All data in this report are from male mice.