Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as , , , , and , were confirmed to be involved in the positive or negative regulation of autophagy in BRCA. was identified firstly as a negative autophagic regulator, and siRNA/shRNA- were shown to induce autophagy-associated cell death in and breast cancer models. Moreover, a novel small-molecule activator of , 1-methylbenzylamino amiodarone, was discovered to induce autophagy and . Together, these results provide multi-omics approaches to identify some key candidate autophagic regulators, such as the negative regulator and positive regulator in BRCA, and highlight and as new druggable targets that could be used to fill the gap between autophagy and cancer drug development.