Hypoxia-related gene DDIT4 as a therapeutic biomarker promotes epithelial-mesenchymal transition in lung adenocarcinoma via the MAPK/ERK signaling pathway.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, yet targeted and immune therapeutic strategies remain limited. DNA damage-inducible transcript 4 (DDIT4) is one of the hypoxia-related genes, and its role in tumors has begun to gain attention. However, the specific mechanism of DDIT4 in LUAD is still unclear. Therefore, in-depth exploration of its role and mechanism in LUAD has high clinical value and innovative significance, and can provide a new direction for the diagnosis and treatment of LUAD. Bioinformatics analysis identified DDIT4 as a poor prognostic factor positively correlated with epithelial-mesenchymal transition (EMT). Tumors with high DDIT4 expression exhibited increased immune infiltration and significantly higher levels of immune checkpoint genes, including PD-L1 and PD-1. Drug sensitivity analysis suggested that DDIT4 could serve as a predictive biomarker for LUAD therapy response. Experimental validation demonstrated that DDIT4 expression was significantly upregulated in LUAD tissues and further induced under hypoxic conditions. Pathway enrichment analyses indicated that DDIT4 may regulate LUAD progression via the MAPK/ERK signaling pathway. Functional experiments confirmed that DDIT4 promotes LUAD cell migration, invasion, and EMT through this pathway. Rescue experiments further validated the mechanistic role of DDIT4, and in vivo studies confirmed its ability to enhance LUAD metastasis. In conclusion, DDIT4 functions as a prognostic biomarker and therapeutic target in LUAD by modulating EMT and metastasis through MAPK/ERK signaling. Its association with immune infiltration and therapy response suggests that targeting DDIT4 may enhance immunotherapy and personalized treatment strategies for LUAD patients.