Pan‐caspase inhibition diminished the elevated caspase‐3/7 activity and reduced the subG1 population in these cells; (ii) Knockdown of ATG4D inhibited migration, invasion, and tumorsphere formation in osteosarcoma cells; (iii) Silencing ATG4D led to an increase in LC3 puncta, as well as the accumulation of LC3‐II and p62, suggesting a disruption in autophagic flux. Here, SQSTM1 is linked to osteosarcoma.