In the current study, we provide for the first time comprehensive and in-depth knowledge of the critical role of a newly identified serum exosomal miRNA miR-4256, which is a 64 nt small noncoding RNA molecule that is approximately three times longer than common miRNAs, in the progression of GC via the SMAD2/miR-4256/HDAC5/p16INK4a axis. This evidence concerns the gene CDKN2A and gastric cancer.