Inhibition of E2F5‐Drp1 complex formation by site‐directed mutagenesis of E2F5 attenuates HPV‐E7/ceramide‐mediated lethal mitophagy, whereas restoring Drp1 activation by ectopic expression of HPV‐E7 or treatment with E2F5‐peptide mimetic (to reconstitute E2F5‐pept‐Drp1 interaction) enhances ceramide‐dependent mitophagy and tumor suppression in HPV(−) HNSCC in culture and in mice. The gene discussed is E2F5; the disease is neoplasm.