CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.

Despite effective first-line regimens, some patients with diffuse large B-cell lymphoma (DLBCL) still experience relapse or resistance, emphasizing the urgent need for innovative treatment approaches. Cytidine triphosphate synthase 1 (CTPS1) is a key regulatory and rate-limiting enzyme for de novo nucleotide synthesis pathway. However, the role of CTPS1 in DLBCL and its potential therapeutic value remain unknown. We found that high levels of CTPS1 were associated with poor prognosis in patients with DLBCL. The single-cell RNA sequencing (scRNA-seq) revealed that phospholipid metabolism and mitophagy-related pathways were activated in DLBCL cells with high CTPS1 expression. Mechanistically, CTPS1 up-regulated the expression of choline/ethanolamine phosphotransferase 1 (CEPT1) by increasing CTP availability, thereby reprogramming glycerophospholipid metabolism. The glycerophospholipids synthesized by CEPT1 maintained mitochondrial homeostasis and promoted BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, ultimately driving the DLBCL progression. Moreover, highly selective CTPS1 inhibitor R80 could reduce the viability of DLBCL cells.