Update publication information The abnormal induction of macroautophagy/autophagy, a highly conserved lysosome-based degradation pathway, has been postulated as a major toxicity of nanomaterials, whereas little is known on the exact molecular mechanisms. Here, we treated mammalian cells with 16 nm silica nanoparticles (SiNPs), conducted a transcriptomic, proteomic and phosphoproteomic profiling during autophagy, and detected up to 7208 (25.09%) genes potentially regulated in at least one level. To identify key regulators, we developed a new algorithm of computational prediction of master protein kinases (cMAK) to integrate the multi-omics data. Using cMAK, we predicted 21 candidates and validated a Cdk7-Cdk4 cascade to be functionally important, while the silence or inhibition of Cdk4 or Cdk7 significantly attenuated the autophagic induction and greatly diminished autophagosome formation. Our studies not only established a powerful method for predicting potentially regulatory kinases from the multi-omics data, but also revealed a novel mechanism of SiNPs-triggered autophagy through activating the Cdk7-Cdk4 cascade.