Multi-omics unveils BCAA metabolism markers L-leucine and HMGCS1 as prognostic marker for immunotherapy efficacy in non-small cell lung cancer

作者：Liyuan Dai, Xinzheng Wang, Ning Lou, Lin Li, Li‐Ling Huang, Le Tang, Jiarui Yao, Yuankai Shi, Xiaohong Han · 发表于：Respiratory Research · 年份：2025 · DOI：10.1186/s12931-025-03277-8 · 被引用次数：6 · 研究领域：Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism、Cancer Immunotherapy and Biomarkers

This study aims to identify branched-chain amino acid (BCAA) plasma metabolites and gene signatures that enhance prognostic assessments in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. Plasma metabolites were measured using untargeted UPLC-MS/MS ( n = 94 and 40), with lymphocyte subset tests on 72 patients. BCAA-related subtypes were identified in NSCLC datasets ( n = 274, 176, and 196). A prognostic risk model was developed and validated in NSCLC ( n = 16, 27, 24, and 339), melanoma ( n = 25), and pan-cancer ICIs cohorts ( n = 330 and 81). Immune cell infiltration and prognostic signatures were validated using mIF ( n = 21 in CHCAMS), scRNA-seq ( n = 8 and 21), and spatial transcriptomics ( n = 2 and 6). Cell and animal experiments involving HMGCS1 were conducted in a lung cancer model. Additionally, based on our previous findings that B cells with higher malignancy exhibited enhanced cholesterol homeostasis pathways in diffuse large B-cell lymphoma (DLBCL), we further analyzed the prognostic value of HMGCS1 using our spatial transcriptomics ( n = 10) and immunohistochemistry (IHC, n = 39) in DLBCL. Our plasma metabolite analysis showed higher L-leucine levels were associated with better prognosis and had higher T cell counts and CD4 + T cell counts ( P < 0.05). In GEO datasets, four NSCLC subtypes were identified, showing distinct prognostic outcomes and tumor microenvironment. Five BCAA-related genes ( ACAT2, ALDH2, HMGCS1, MLYCD, and PPM1 K ) formed...