Although more data are needed to clarify the impact of HSPD1 expression on osteosarcoma progression and the immune microenvironment, our study describes for the first time that HSPD1 inhibits K48 ubiquitination degradation of ATP5A1, which facilitates mitochondrial ATP production and activation of AKT/mTOR signaling. The gene discussed is ATP5F1A; the disease is osteosarcoma.