Moreover, ZnONPs alone substantially activated caspase-9 and -3 in A549 cells at much higher concentrations (10–80 μg/mL) compared to MTX-ZnONPs (at the dose of 100–800 ng/mL) and MTX alone (at the dose of 1–8 μg/mL), while there was no significant activation of caspase-8, illustrating the activation of only the mitochondrial pathway of programmed cell death in lung cancer cells treated with ZnONPs at higher concentrations. Here, CASP8 is linked to lung cancer.