E2F5 and neoplasm: We demonstrate here that inhibition of retinoblastoma protein (RB) by the HPV‐E7 oncoprotein relieves E2F5, which then associates with Drp1 as a scaffolding protein, resulting in Drp1‐mediated mitochondrial fission, induction of ceramide‐dependent lethal mitophagy, and tumor suppression.