Asparaginase removes asparagine supply from the extracellular environment creating an asparagine-starved environment. At the cellular level, asparagine starvation causes the activation of the amino acid response mechanism triggered by the presence of uncharged transfer RNAs and initiated by the general control nonrepressible-2 (GCN2) kinase. GCN2 activation has a double downstream effect: it induces expression of stress response proteins by activating the eukaryotic initiation factor 2 (eIF2a)-activating transcription factor 4 (ATF4) transduction axis and it represses general protein synthesis by repressing Akt/mTORC1 activity. Failure in expression of stress response proteins such as asparagine synthetase (ASNS) causes activation of proautophagy mechanisms and, eventually, apoptosis. Lee et al described a new route for asparaginase proapoptotic signaling that involves the activation of the protease-activated receptor 2 (PAR2)/InsP₃R Ca²⁺-mediated pathway. Failure in its activation because of HAP1 loss has a relevant effect on the capability of asparagine starvation to trigger apoptosis in leukemia cells.