Figure 6.

PEG-ASNase leads to adipose tissue lipolysis via an unknown mechanism. PEG-ASNase leads to asparagine depletion that induces general control nonderepressible 2 (GCN2) kinase-dependent activation of the amino acid response (AAR) via phosphorylation of eIF2α. We hypothesize that the AAR leads to activation of adenylyl cyclase due to our studies indicating that PEG-ASNase or cycloheximide treatment, which both induce phosphorylation of eIF2α, leads to activation of PKA and HSL. Altogether, we posit that PEG-ASNase-induced liver injury is due to ATGL activation by the chemotherapeutic agent. Figure created with BioRender.com.