ARL5B Drives Esophageal Squamous Cell Carcinoma Progression via ROCK1–SREBP1‐Mediated Lipid Metabolic Reprogramming

Abstract Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with a 5 year survival rate below 30%, underscoring the urgent need for targeted therapeutic approaches. 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. Through the Cancer Genome Atlas (TCGA) pan‐cancer analysis, ARL5B is initially identified as a promising candidate gene, correlating with advanced tumor, node, metastasis (TNM) stages and poor survival. Functional assays demonstrate that ARL5B knockdown significantly suppresses cell proliferation, invasion, and growth in vivo, while promoting apoptosis. Mechanistically, ARL5B facilitates the activation and nuclear translocation of SREBP1 through ROCK1, thereby enhancing lipogenic programming. Finally, pharmacological inhibition of either ROCK1 or SREBP1 abrogates the oncogenic effects induced by ARL5B overexpression, confirming the functional dependency on this pathway. These results establish ARL5B as a central regulator of lipid metabolism in ESCC and highlight its potential as a therapeutic target for precision oncology.