Hyperlactataemia in lymphoma-associated haemophagocytic lymphohistiocytosis: Linked to monocytic glycolysis and adverse prognosis.

Lymphoma-associated haemophagocytic lymphohistiocytosis (HLH) represents a rare and life-threatening hyperinflammatory syndrome with a dismal prognosis, largely due to its poorly understood pathogenesis and unclear distinctions from non-lymphoma associated HLH (NLAHS). To elucidate these differences, we performed an integrated multiomics analysis on peripheral blood samples from patients with newly diagnosed lymphoma-associated HLH (LAHS), NLAHS and healthy controls (NC). Single-cell ribonucleic acid sequencing (scRNA-seq) analysis (4 LAHS, 3 NLAHS, 2 NC) revealed that LAHS is characterized by enhanced glycolytic activity in significantly expanded monocyte populations, notably within a distinct subset of pituitary tumor-transforming gene 1+ (PTTG1+) monocytes. Metabolomic profiling (21 LAHS, 11 NLAHS, 7 NC) further confirmed elevated levels of glycolytic products, such as lactate and pyruvate. Clinically, hyperlactataemia (>5.1 mmol/L, n = 84) emerged as a significant independent predictor of poor survival in LAHS, with a median overall survival of only 43.5 days (p < 0.001). Remission induced by treatment was associated with a reversal of this hypermetabolic phenotype. Cell communication analysis revealed upregulated thrombospondin signalling from PTTG1+ monocytes, linked to glycolytic activity. Our findings indicate that LAHS is characterized by a pronounced Warburg-like metabolic state, primarily involving glycolytic monocytes. Hyperlactataemia is associated with adverse outcomes and may guide the development of novel therapeutic strategies targeting immunometabolic pathways.