Here adenosine diphosphate (ADP)‐ribosylation factor‐like protein 5B (ARL5B) is identified as a key candidate oncogene that drives ESCC progression by modulating lipid metabolism via the ras homologous‐associated coiled‐coil containing protein kinase 1(ROCK1)–sterol regulatory element‐binding protein 1 (SREBP1) signaling axis. The gene discussed is ARL5B; the disease is esophageal squamous cell carcinoma.