The FGD5-AS1/miR-142-5p/CDK5 axis promotes ESCC progression by regulating mitochondrial fission and mitophagy: insights from integrative bioinformatics and experimental analyses.

Esophageal squamous cell carcinoma (ESCC) continues to pose a significant health challenge worldwide because of its poor prognosis and limited therapeutic options. To identify key regulators, we performed integrative bioinformatic approaches, such as differential expression analysis, weighted gene co-expression network analysis (WGCNA), LASSO regression, support vector machine (SVM) modeling, and ceRNA network construction, followed by experimental validation. These analyses across three GEO cohorts consistently highlighted FGD5-AS1 and CDK5 as upregulated, while miR-142-5p was downregulated and emerged as a central regulator within the ceRNA network. Clinical samples and functional assays confirmed these findings, showing that FGD5-AS1 overexpression enhanced proliferation, invasion, and migration while suppressing apoptosis in ESCC cells. Moreover, FGD5-AS1 promoted mitochondrial fission and mitophagy through miR-142-5p sequestration, leading to increased CDK5 levels, thereby driving tumor progression. Animal experiments further demonstrated that modulation of FGD5-AS1 expression significantly altered tumor growth. Collectively, these integrative results reveal that the FGD5-AS1/miR-142-5p/CDK5 axis promotes ESCC malignancy by regulating mitochondrial dynamics, suggesting that the FGD5-AS1/miR-142-5p/CDK5 axis may represent a candidate molecular target and warrants further investigation for its potential clinical relevance in ESCC.