Elevated UBE2L6 Expression Predicts Poor Prognosis and Is Associated With Fatty Acid Metabolic Remodeling in Esophageal Cancer

Ubiquitin‐conjugating enzyme E2L6 (UBE2L6) is a molecule involved in the regulation of fatty acid metabolism, and previous studies have shown that it promotes tumor cell proliferation. However, the functional role of this molecule in esophageal cancer (ESCA) remains unclear. Here, we investigated UBE2L6 expression, its association with clinicopathological features, and its impact on fatty acid metabolites in ESCA. Differentially expressed genes between ESCA and adjacent normal tissues were screened from the Gene Expression Omnibus database using weighted gene co‐expression network analysis (WGCNA). UBE2L6 expression was examined via GEPIA and immunohistochemistry, and correlations with clinical features were analyzed using UALCAN. Functional studies were performed by UBE2L6 knockdown and overexpression in ESCA cells, evaluating proliferation, migration, and cell cycle. Metabolomic profiling was conducted to assess fatty acid metabolites. UBE2L6 was upregulated in ESCA with high diagnostic accuracy (AUC = 0.889). Its expression was significantly associated with sample type, histological grade, stage, and lymph node metastasis (all p < 0.05). UBE2L6 knockdown suppressed proliferation and migration, induced G0/G1 arrest and reduced the S‐phase population, whereas overexpression elicited opposite effects. Metabolomic analysis showed that UBE2L6 overexpression downregulated arachidonic acid and its downstream metabolites and decreased levels of key fatty acids. UBE2L6 critically contributes to ESCA progression and fatty acid metabolism modulation. These results enhance molecular insight into UBE2L6 and suggest metabolic regulation as a potential therapeutic avenue for ESCA.