In this study, we first demonstrated that i) MTA metabolic reprogramming plays a core regulatory role in the epigenetic‐autophagy axis in the context of Cd‐induced BC malignancy; ii) Cd‐induced MTA depletion specifically decreases DOT1L methyltransferase activity and increases H3K79me1 levels in the PAK2 promoter region, promoting the expression of PAK2, which contributes to the autophagic flux blockade required for BC progression; and iii) MTA levels negatively correlate with BC tumor stage, thereby substantiating the clinical importance of MTA depletion in BC progression. Here, PAK2 is linked to breast cancer.