Abstract

Our previous studies demonstrated that the fat mass and obesity-associated protein (FTO) is upregulated in colorectal cancer (CRC). It demethylates G6PD/PARP1 and SLC7A11/GPX4 mRNAs, thereby protecting CRC from DNA damage and ferroptotic cell death. However, the mechanisms underlying FTO upregulation in CRC remain unclear. Unexpectedly, we show Ubiquitin-specific peptidase 30 (USP30) binds serine/glycine and senses their levels to protect FTO from proteosome degradation. Stabilized FTO demethylates 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) mRNAs and inhibits their degradation in an m 6 A-YTHDF2-dependent manner, thereby promoting serine synthesis and CRC tumor growth. Furthermore, we identify sodium 2, 2-dichloroacetate (DCA) as a novel inhibitor of USP30, and DCA inhibits CRC serine synthesis and tumor growth. Clinically, USP30, FTO, PHGDH, and PSAT1 levels are highly correlated in CRC tissues. This study provides mechanistic insights into how USP30 senses serine/glycine levels to regulate serine synthesis via the FTO-PHGDH/PSAT1 axis, offering a potential therapeutic strategy for targeting serine/glycine metabolism in cancer.