Here, for the first time, we reported that neddylation inhibition by CPT significantly induced the accumulation of p-IκBα to trigger pro-survival autophagy by modulating NF-κB/AMPK/mTOR/ULK1 axis in esophageal cancer cells, highlighting targeting autophagy as a potential strategy to enhance anti-ESCC therapy of CPT. The gene discussed is NFKB1; the disease is esophageal squamous cell carcinoma.