Further investigations revealed that HDAC2 interacted with DHX15, downregulated Kla at the K17 site and might reverse DHX15’s tumor-suppressive function through regulating alternative splicing of RPL9. These findings collectively demonstrate that HDAC2, as a delactylase, dynamically shapes BCa progression by orchestrating the Kla of critical proteins, forming a sophisticated regulatory network. Here, RPL9 is linked to neoplasm.