As a downstream target of α2δ1‐mediated calcium signaling, SIRT4 serves as an oncogene to promote the stemness of pancreatic cancer via deacetylating ENO1 directly at K358, leading to attenuated ENO1's RNA‐binding capacity, enhanced glycolytic substrate 2‐PG binding and robust glycolytic activity to increase the level of lactate that induce histone lactylation to epigenetically regulate signaling pathways essential for stemness. Here, ENO1 is linked to familial pancreatic carcinoma.