All the above findings suggested that PKCiota overexpression caused by PRKCI amplification and loss of miR-145-5p enhanced the phosphorylation of USP14 at Ser sites and subsequentially reduced the ubiquitination of GPX4, then improved the protein stability of GPX4 via suppressing the autophagy–lysosomal degradation pathway via forming a protein complex including PKCiota, USP14, and GPX4, and finally induced the resistance of ESCC cells to ferroptosis. This evidence concerns the gene PRKCI and esophageal squamous cell carcinoma.