Uridine metabolism promotes lung adenocarcinoma progression by activating FBL transcription via YBX1.

[BACKGROUND] Uridine metabolism serves as a critical compensatory metabolic pathway in tumor cells under glucose deprivation. However, the mechanistic role of uridine metabolism in tumorigenesis and progression has not been elucidated.

[METHOD] Distinct uridine metabolism patterns across pan-cancer types were analyzed using the TCGA database. Single-cell RNA sequencing was used to delineate uridine metabolic variations within the tumor microenvironment (TME). Through comprehensive bioinformatics analyses, including enrichment and transcription factor network mapping, YBX1 was identified as a key downstream transcriptional regulator. RNA sequencing, chromatin immunoprecipitation quantitative PCR (ChIP-qPCR), and immunoprecipitation (IP) assays were used to explored the key regulatory targets of the transcription factor. Furthermore, the role of YBX1 in promoting tumor progression via ribosome biogenesis was further investigated.

[RESULT] Pan-cancer analyses demonstrated a strong correlation between elevated uridine metabolism levels and unfavorable clinical outcomes, particularly in lung adenocarcinoma (LUAD). Single-cell analysis revealed that uridine metabolism promoted ribosomal biogenesis and identified YBX1 as the key transcription factor responsible for this regulation. Mechanistically, we found that uridine metabolism led to YBX1 lactylation at the K137 site, thereby stabilizing the YBX1 protein. By integrating RNA-sequencing and ChIP-qPCR assays, we found that YBX1 transactivated FBL expression by directly binding to its promoter, thereby modulating ribosome biogenesis. Functional assays demonstrated that silencing either YBX1 or FBL inhibited tumor cell proliferation, migration, and stemness. In vivo, we validated that knockdown of YBX1 or FBL significantly reduced tumor growth in mice. Moreover, our rescue experiments provided causal evidence that FBL knockdown could abrogate the oncogenic phenotypes of YBX1 overexpression both in vitro and in vivo.

[CONCLUSION] Our findings not only highlight the uridine metabolism-YBX1-FBL axis as a potential oncogenic mechanism but also provide a framework for developing targeted therapies against uridine metabolic pathways. Clinically, these results potentially enable metabolic profiling-based patient stratification, paving the way for personalized treatment strategies in LUAD management.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-026-08034-z.