Glucocorticoid and mitophagy signaling–based molecular subtyping reveals HMGA1 as a prognostic and immunotherapy biomarker in lung adenocarcinoma
- 1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine; Key Laboratory of Cancer Prevention and Therapy, Tianjin, PR China
- 2Tianjin’s Clinical Research Center for Cancer; Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, PR China
- 3Shanxi Medical University, Taiyuan, PR China
Abstract
Lung adenocarcinoma (LUAD) shows marked heterogeneity, limiting the effectiveness of traditional classifications. We integrated bulk transcriptomic data from TCGA and multicenter cohorts with spatial transcriptomics for in situ validation. Analysis of glucocorticoid (GC) and mitophagy pathways identified 127 core genes, enabling a novel molecular subtyping and survival risk model that predicted prognosis and correlated with immune infiltration. High mobility group AT-hook 1 (HMGA1) emerged as a key regulator of tumor metabolism, immune evasion, and therapy resistance. Spatial transcriptomics with RCTD-based deconvolution showed a tumor-enriched and heterogeneous HMGA1 expression pattern and a positive spatial association with epithelial cell proportion in tumor sections. Single-cell RNA-seq analysis further resolved HMGA1 enrichment to tumor epithelial cells, and CIBERSORTx projection linked the HMGA1-high tumor epithelial cell state to poor prognosis and increased proliferation. Functional assays showed that high HMGA1 expression conferred sensitivity to metabolic inhibitors but resistance to proteasome inhibitors, while HMGA1 knockout suppressed tumor growth and enhanced anti–PD-1 efficacy. By integrating bulk modeling with spatial validation, this study establishes a GC–mitophagy–based classification and highlights HMGA1 as a promising biomarker for prognostic stratification and personalized immunotherapy in LUAD.
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BibTeX
@article{yu2026glucocorticoid,
title = {{Glucocorticoid and mitophagy signaling–based molecular subtyping reveals HMGA1 as a prognostic and immunotherapy biomarker in lung adenocarcinoma}},
author = {Junjie Yu and Yantao Jiang and Qingqing Xiong and Yongmeng Wu and Wei Luo and Luyao Tong and Yi Lu and Lianmin Zhang and Peng Chen and Tingting Qin},
journal = {NPJ Precision Oncology},
year = {2026},
month = jun,
doi = {10.1038/s41698-026-01561-4},
url = {https://doi.org/10.1038/s41698-026-01561-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Glucocorticoid and mitophagy signaling–based molecular subtyping reveals HMGA1 as a prognostic and immunotherapy biomarker in lung adenocarcinoma
AU - Junjie Yu
AU - Yantao Jiang
AU - Qingqing Xiong
AU - Yongmeng Wu
AU - Wei Luo
AU - Luyao Tong
AU - Yi Lu
AU - Lianmin Zhang
AU - Peng Chen
AU - Tingting Qin
PY - 2026
DA - 2026/06/20
JO - NPJ Precision Oncology
DO - 10.1038/s41698-026-01561-4
UR - https://doi.org/10.1038/s41698-026-01561-4
AB - Lung adenocarcinoma (LUAD) shows marked heterogeneity, limiting the effectiveness of traditional classifications. We integrated bulk transcriptomic data from TCGA and multicenter cohorts with spatial transcriptomics for in situ validation. Analysis of glucocorticoid (GC) and mitophagy pathways identified 127 core genes, enabling a novel molecular subtyping and survival risk model that predicted prognosis and correlated with immune infiltration. High mobility group AT-hook 1 (HMGA1) emerged as a key regulator of tumor metabolism, immune evasion, and therapy resistance. Spatial transcriptomics with RCTD-based deconvolution showed a tumor-enriched and heterogeneous HMGA1 expression pattern and a positive spatial association with epithelial cell proportion in tumor sections. Single-cell RNA-seq analysis further resolved HMGA1 enrichment to tumor epithelial cells, and CIBERSORTx projection linked the HMGA1-high tumor epithelial cell state to poor prognosis and increased proliferation. Functional assays showed that high HMGA1 expression conferred sensitivity to metabolic inhibitors but resistance to proteasome inhibitors, while HMGA1 knockout suppressed tumor growth and enhanced anti–PD-1 efficacy. By integrating bulk modeling with spatial validation, this study establishes a GC–mitophagy–based classification and highlights HMGA1 as a promising biomarker for prognostic stratification and personalized immunotherapy in LUAD.
SN - 2397-768X
ER -