The decisive role of USP28 and USP25 in maintaining elevated cellular levels of different ‘hard to drug’ cancer-promoting proteins has rendered both DUBs highly attractive targets for the development of small-molecule inhibitors against different cancers (Popov et al, 2007; Wu et al, 2013; Diefenbacher et al, 2014; Xu et al, 2017; Prieto-Garcia et al, 2020; Nelson et al, 2022). Here, USP25 is linked to cancer.