Hyperlactataemia in lymphoma‐associated haemophagocytic lymphohistiocytosis: Linked to monocytic glycolysis and adverse prognosis
Xuelian Hu, Liangshun You, Jinghan Wang, Xuejiao Yin, Xueying Yang, Xin Huang, Jing Ma, Zhenbo Wang, Hao Shen, Dezhen Wang, Chunmei Yang, Xingnong Ye, Dagan Yang, De Zhou, Hongyan TongSummary
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.