5’‐Methylthioadenosine Metabolic Reprogramming Drives H3K79 Monomethylation‐Mediated PAK2 Upregulation to Promote Cadmium‐Induced Breast Cancer Progression by Impairing Autophagic Flux

Cadmium, a carcinogenic heavy metal, drives breast cancer progression via metabolic reprogramming and autophagic flux disruption. Multi‐omics revealed cadmium‐induced 5'‐methylthioadenosine depletion activates DOT1L‐mediated H3K79me1 at PAK2 promoter, upregulating PAK2 to block autophagy and driving malignancy. Clinically, 5'‐methylthioadenosine levels show a negative correlation with TNM stages in breast cancer patients. This study elucidates metabolism‐epigenetic crosstalk in environmental carcinogen‐promoted breast cancer progression. Abstract Cadmium (Cd) is a heavy metal that exhibits strong carcinogenic properties and promotes breast cancer (BC) progression. Autophagic flux dysfunction is involved in Cd‐induced BC progression, but the underlying molecular mechanisms remain unclear. Here, it is observed that impaired autophagic flux and metabolic reprogramming are notable features related to Cd‐induced proliferation, migration, and invasion in BC cell lines, including T‐47D and MCF‐7 cells. Through the integration of metabolomics, proteomics, and ingenuity pathway analysis, a metabolite–protein regulatory network is constructed, which revealed that 5′‐methylthioadenosine (MTA)‐mediated metabolic reprogramming plays a core regulatory role in the epigenetic‒autophagy axis involved in Cd‐induced autophagic flux impairment and BC progression. Mechanistically, Cd‐induced MTA depletion specifically increased DOT1L methyltransferase activity and H3K79me1 levels in the PAK2 promoter region, inducing the expression of PAK2, which contributed to the autophagic flux blockade required for BC progression in Cd‐exposed BC cells and transgenic MMTV‐ErbB2 mice. Clinically, a significant negative correlation is also verified between MTA levels and TNM stage in BC patients; that is, advanced‐stage tumors exhibited notably lower MTA levels than early‐stage tumors. Thus, the study provides insights into metabolism‒epigenetic crosstalk in the context of Cd‐induced BC progression and highlights the importance of considering environmental factors in cancer healthcare. Cadmium, a carcinogenic heavy metal, drives breast cancer progression via metabolic reprogramming and autophagic flux disruption. Multi-omics revealed cadmium-induced 5'-methylthioadenosine depletion activates DOT1L-mediated H3K79me1 at PAK2 promoter, upregulating PAK2 to block autophagy and driving malignancy. Clinically, 5'-methylthioadenosine levels show a negative correlation with TNM stages in breast cancer patients. This study elucidates metabolism-epigenetic crosstalk in environmental carcinogen-promoted breast cancer progression. Abstract Cadmium (Cd) is a heavy metal that exhibits strong carcinogenic properties and promotes breast cancer (BC) progression. Autophagic flux dysfunction is involved in Cd-induced BC progression, but the underlying molecular mechanisms remain unclear. Here, it is observed that impaired autophagic flux and metabolic reprogramming are notable features related to Cd-induced proliferation, migration, and invasion in BC cell lines, including T-47D and MCF-7 cells. Through the integration of metabolomics, proteomics, and ingenuity pathway analysis, a metabolite–protein regulatory network is constructed, which revealed that 5′-methylthioadenosine (MTA)-mediated metabolic reprogramming plays a core regulatory role in the epigenetic‒autophagy axis involved in Cd-induced autophagic flux impairment and BC progression. Mechanistically, Cd-induced MTA depletion specifically increased DOT1L methyltransferase activity and H3K79me1 levels in the PAK2 promoter region, inducing the expression of PAK2, which contributed to the autophagic flux blockade required for BC progression in Cd-exposed BC cells and transgenic MMTV-ErbB2 mice. Clinically, a significant negative correlation is also verified between MTA levels and TNM stage in BC patients; that is, advanced-stage tumors exhibited notably lower MTA levels than early-stage tumors. Thus, the study provides insights into metabolism‒epigenetic crosstalk in the context of Cd-induced BC progression and highlights the importance of considering environmental factors in cancer healthcare. Advanced Science, Volume 12, Issue 44, November 27, 2025.