RFWD3 Reprograms Nucleotide Metabolism Through PHGDH to Induce Chemoresistance In Osteosarcoma.

ABSTRACT: Chemoresistance represents a major challenge for osteosarcoma treatment. Despite the improved knowledge of cancer biology, the core determinants of cisplatin (DDP) resistance in osteosarcoma remain unclear and deserve further exploration. Here, RFWD3 is identified as a key regulator of DDP sensitivity in osteosarcoma using a genome-wide CRISPR screen. It is demonstrated that RFWD3 is overexpressed in post-chemotherapy osteosarcoma tissues compared to pre-chemotherapy tissues. Knocking out RFWD3 increased the sensitivity of osteosarcoma cells to DDP treatment. Mechanistically, RFWD3 bound to and ubiquitinated PHGDH at the Lys137 residue, promoting its degradation and conserving cellular oxidized nicotinamide adenine dinucleotide (NAD⁺). The resulting surplus of NAD⁺ en

SUBMITTER: Zhang W 

PROVIDER: S-EPMC12021087 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature