Dapk2, a member of the death-associated kinase (DAPK) protein family, is a Ca(2+)-regulated serine/threonine kinase. It acts as a tumor suppressor and is involved in crucial cellular processes such as apoptosis, autophagy, and mitochondrial function regulation [1,2,4]. It interacts with various proteins and signaling pathways like TNF, IFN, AMPK, mTORC1, p73, and JNK [1].

Genetic studies show that Dapk2 knockdown reduces autophagy triggered by amino acid deprivation or increased intracellular Ca(2+) levels, as it interferes with mTORC1 inhibition [2]. In cancer cells, RNA interference-mediated depletion of Dapk2 leads to metabolic changes, decreased oxidative phosphorylation, and increased oxidative stress due to mitochondrial membrane potential destabilization [4]. In human obesity, Dapk2 downregulation in adipocytes is associated with attenuated autophagic clearance, and its overexpression in adipocytes increases autophagic clearance [3]. Also, genetic ablation of Dapk2 in cancer cell lines causes phosphorylation of NF-κB and induction of proapoptotic DR4 and DR5, sensitizing resistant cells to TRAIL-induced killing [5].

In summary, Dapk2 is essential for regulating autophagy, mitochondrial function, and apoptosis. Model-based research, especially loss-of-function experiments, has revealed its significance in cancer and obesity. In cancer, it plays a role in tumor suppression through regulating autophagy and apoptosis, and in obesity, it is involved in adipocyte autophagic clearance, providing potential therapeutic targets for these diseases.