DDP‐resistant cells exhibit a heightened activation of DNA repair pathways to mitigate the deleterious effects of DNA damage.[26] Our previous studies have demonstrated that disturbance of the DNA repair pathway could sensitize osteosarcoma to chemotherapy.[2, 27] RFWD3 is involved in multiple DNA repair processes, including RPA‐mediated DNA damage repair and the regulation of p53 stability.[9, 28] However, our current study reveals that, in addition to its direct role in DNA repair, RFWD3 also modulates nucleotide metabolism in osteosarcoma. Here, RFWD3 is linked to osteosarcoma.