?BACKGROUND: Esophageal cancer (EC) ranks among the most lethal cancers worldwide, comprising the histological subtypes squamous cell carcinoma and adenocarcinoma (EAC), both of which present poor prognoses and low 5-year overall survival rates. Understanding the underlying mechanisms of EC progression is crucial for identifying potential therapeutic targets. In this context, the HMGA genes are overexpressed in various tumors and influence tumor progression in vivo by encoding HMGA1 and HMGA2 proteins, which regulate gene transcription. Investigating the role of HMGA in EC, primary analysis of our group identified HMGA1 overexpression in EAC samples. OBJECTIVE: Thus, the main objective of this work was to investigate the involvement of HMGA1 in the progression of EAC. METHODS: Translational, in vitro and in silico approaches were employed. The in vitro model was based on HMGA1 silencing, using a siRNA targeting HMGA1 mRNA (siHMGA1), in two EAC cell lines, OE19 and OE33. RESULTS: siHMGA1 reduced proliferation, migration, invasion and increased apoptosis of both cell lines. Exploring the potential underlying mechanism, analysis of TCGA-deposited EAC data identified the cell cycle as the main deregulated process and CCNE1, which encodes Cyclin E1, as a differentially expressed gene positively correlated with HMGA1 mRNA levels. Indeed, siHMGA1 reduced CCNE1 expression in vitro. Interestingly, while siHMGA1 alone did not significantly alter the cell cycle profile, it led to HMGA2 upregulation by silencing mir196a2, which in turn activated CDC6. This suggests a potential interplay between HMGA1, HMGA2 and CDC6 in regulating the cell cycle in EAC, which might explain the limited impact of siHMGA1 on the cell cycle profile despite reduced CCNE1 levels. Furthermore, silencing both HMGA1 and HMGA2 resulted in a significant reduction in the S phase population in OE33 cells. CONCLUSIONS: Collectively, these data suggest that HMGA1 may contribute to the progression of EAC, potentially through its involvement in cell cycle deregulation and may be a potential therapeutic target for this tumor.