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Identification of Inflammatory Cell Death-Related Prognostic Signature and Its Regulatory Mechanism in Lung
Yalun Yang1,2, Di Liu1,2, Shengwei Ma1,2
1Jingzhou Central Hospital, Jingzhou, China.
Objective:
This study investigated how inflammatory cell death-associated regulators influence the prognosis of lung adenocarcinoma (LUAD) and elucidated their underlying mechanisms.
Methods:
LUAD RNA-seq data from UCSC-Xena (training) and GSE72094 (validation) were analyzed. Inflammatory cell death regulators were identified, and LUAD subtypes were classified based on their expression. Subtypes were compared with respect to prognosis, clinical features, immune microenvironment, HLA genes, and immune checkpoints. Prognosis-related regulators and independent factors were identified, and a RiskScore model was built. Genomic alterations, drug sensitivity, immunotherapy response, and metabolic differences were analyzed across risk-stratified cohorts. Knockdown of TFDP1 in A549 cells was performed in vitro, and its effects on cell function were evaluated via RT-qPCR, Western blot, CCK-8, Transwell, and flow cytometry.
Results:
The research revealed 15 upregulated and 9 downregulated genes associated with inflammatory cell death, which were employed to stratify LUAD cases into two subtypes (Cluster 2 exhibited longer overall survival and higher immune/stromal scores). The seven-gene prognostic model (comprising BAK1, BMF, CYCS, FADD, IL1A, TFDP1, and YWHAG) demonstrated robust predictive power for LUAD patient survival risk. Notably, the high-risk cohort exhibited higher TIDE scores and lower IPS scores than the low-risk group. IL1A was positively correlated with 11 immune cell types and negatively correlated with 4. Drugs such as docetaxel and parthenolide may target this model. The study identified significant differences in 14 metabolic pathway enrichments between risk groups, particularly in fatty acid and fructose metabolism. Experimental validation confirmed TFDP1 upregulation in LUAD, and its knockdown suppressed A549 cell proliferation, migration, and invasion while inducing apoptosis.
Conclusion:
A seven-gene inflammatory cell death-based signature for LUAD was developed, highlighting its role in immune regulation and its potential for immunotherapy. Experimental validation identified TFDP1 as a key regulator of inflammatory cell death processes in LUAD progression.
