An SDHB-based prognostic signature uncovers lactate-dependent metabolic and immune regulation in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by extensive metabolic reprogramming and a highly immunosuppressive microenvironment, yet the mechanisms linking metabolic alterations to immune regulation and therapeutic response remain incompletely understood. In this study, hypoxia- and lactate metabolism–related genes were systematically screened, and a prognostic model was constructed based on transcriptomic and clinical data. Succinate dehydrogenase subunit B (SDHB) was identified as an independent adverse prognostic factor, with elevated SDHB expression consistently associated with poorer overall survival in both training and validation cohorts. Integrated analyses further suggested that SDHB expression was related to immune cell infiltration patterns, immune checkpoint molecules, and stromal components, implying a potential role in shaping the leukemia microenvironment. Functional experiments in THP-1 and HL-60 cells showed that SDHB knockdown was accompanied by reduced lactate-related metabolic activity, including decreased LDHA and MCT4 expression, lower intracellular and extracellular lactate levels, reduced glucose consumption and ATP production, and increased apoptosis. These effects were partially attenuated by exogenous lactate supplementation, suggesting that SDHB may contribute to metabolic adaptation in a lactate-dependent manner. In addition, SDHB silencing enhanced cytarabine sensitivity, which could be partly reversed by lactate treatment, indicating a possible link between metabolic state and drug response. Immunofluorescence analysis further showed that SDHB expression was associated with MCT4 levels at the cellular level, although whether this regulation is direct or secondary to metabolic changes requires further investigation. Collectively, these findings suggest that SDHB may participate in the coordination of metabolic remodeling, immune context, and therapeutic response in AML, and could represent a potential biomarker for risk stratification.