STAT1 is a potential prognostic biomarker in lung adenocarcinoma regulated by hsa-miR-145-3p and hsa-let-7b-5p

BACKGROUND: Signal transducer and activator of transcription 1 (STAT1) is a key transcription factor with context‑dependent tumor‑suppressive and tumor‑promoting functions, yet its prognostic and immunologic roles in lung adenocarcinoma (LUAD) remain incompletely defined. This study aimed to characterize STAT1 expression in LUAD, investigate its association with both clinical outcome and the tumor immune microenvironment, and study its potential regulation by microRNAs. METHODS: We integrated TCGA‑LUAD and GEO (GSE31210) datasets with public bioinformatics tools to evaluate STAT1 expression in LUAD versus normal lung tissue, the clinicopathological stages, and to assess its association with overall survival. Within STAT1‑upregulated LUAD, we applied consensus clustering to define transcriptomic subclasses and characterized their immune‑cell infiltration and overall survival. To further explore STAT1‑associated functional effect, we conducted pathway analyses for the IFN‑γ response and MYC‑driven proliferative pathway using the Hallmark gene sets "INTERFERON_GAMMA_RESPONSE" and "MYC_TARGETS_V1," respectively. Next, we examined the correlation between STAT1 and checkpoints expression levels. Moreover, we used miRNet to identify STAT1‑related microRNAs, followed by expression and correlation analyses using StarBase and survival analysis in Kaplan-Meier Plotter. RESULTS: our results revealed that STAT1 expression was significantly upregulated in LUAD compared with normal lung tissue and across the pathological stages, with higher STAT1 levels associated with poorer overall survival. Within STAT1‑upregulated LUAD, consensus clustering identified distinct three transcriptomic subclasses that differed in immune‑cell infiltration yet showed no significant differences in overall survival. In STAT1‑upregulated LUAD, IFN‑γ response and MYC proliferative activity showed opposite trends across the three subtypes. Subtype 2 had the strongest interferon signaling but the lowest MYC‑driven proliferation, while Subtypes 1 and 3 displayed higher MYC activity with reduced IFN‑γ response. This indicates an inverse relationship between inflammatory (IFN‑γ‑dominant) and proliferative (MYC‑driven) phenotypes. STAT1 expression correlated positively with PD‑1 and PD‑L1 levels, indicating linkage to immune checkpoint upregulation. We identified STAT1‑related microRNAs using miRNet database. We found hsa‑let‑7b‑5p and hsa‑miR‑145‑3p were downregulated in LUAD, inversely correlated with STAT1, and associated with worse survival in Kaplan-Meier analyses. CONCLUSION: STAT1 is upregulated in LUAD and associated with poor prognosis and immune checkpoint upregulation. The STAT1-hsa‑let‑7b‑5p/hsa‑miR‑145‑3p axis emerges as a potential regulatory axis in LUAD.