To address chemoresistance, Jiang et al. demonstrated that ubiquitin-conjugating enzyme E2 T (UBE2T) promotes pyrimidine biosynthesis and alleviates replication stress, leading to gemcitabine resistance by catalyzing the ubiquitination-dependent degradation of p53 and alleviating the transcriptional repression of RRM1 and RRM2 [205] Combining gemcitabine with a UBE2T inhibitor not only significantly improved long-term survival in spontaneous PC mouse models but also markedly reduced tumor growth in humanized models. This evidence concerns the gene TP53 and pachyonychia congenita.