TYR and melanoma: By taking advantage of the potent catalytic activity of TYR that is mechanistically validated by ab initio molecular dynamics (AIMD) theoretical calculation and experimental catalysis performance, we develop a TYR-catalyzed in-situ formed proteolysis-targeting chimeras (PROTACs) to degrade intracellular TYR protein to decrease melanin synthesis for treating hyperpigmentation and a TYR-catalyzed in-situ activated prodrug strategy to overcome drug resistance for melanoma therapy.