biostudies-literatureWu CNational Natural Science Foundation of ChinaGuangdong provincial funding awards9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12809899biostudies-literatureUnknown19(1)The survival mechanisms of circulating tumor cells (CTCs) remain poorly understood while these rare cell populations transit through the blood stream and colonize distant organs including the brain. Using single-cell RNA-seq of microfluidically-enriched CTCs and patient-matched brain metastatic tumor cells of lung adenocarcinoma (LUAD), we revealed CTC-selective upregulation of core gene signatures associated with ferroptosis. The malignancy of CTCs was confirmed through comparative genomic instability and copy number variation (CNV) analyses of paired CTCs and metastatic tumor cells using both transcriptomic and whole-exome sequencing. Among the transcription factors elevated in CTCs, Chromobox 3 (CBX3) was the top hit, which was tightly correlated with GPX4 expression. Functionally, CBX3Journal of hematology & oncologyCBX3 confers ferroptosis resistance during blood-borne metastasis.PMC12809899824B20892021QN02Y1128217339182203397Zhao BHuang GTan JGuo WWu CZheng SCheng YLiu XZhao MGuo LHong XHu JZhang BfalseCBX3 confers ferroptosis resistance during blood-borne metastasis.The survival mechanisms of circulating tumor cells (CTCs) remain poorly understood while these rare cell populations transit through the blood stream and colonize distant organs including the brain. Using single-cell RNA-seq of microfluidically-enriched CTCs and patient-matched brain metastatic tumor cells of lung adenocarcinoma (LUAD), we revealed CTC-selective upregulation of core gene signatures associated with ferroptosis. The malignancy of CTCs was confirmed through comparative genomic instability and copy number variation (CNV) analyses of paired CTCs and metastatic tumor cells using both transcriptomic and whole-exome sequencing. Among the transcription factors elevated in CTCs, Chromobox 3 (CBX3) was the top hit, which was tightly correlated with GPX4 expression. Functionally, CBX32026-01-01T00:00:00Z2026 Jan2026-06-06T14:44:27.47Z2026-06-01T03:07:03.64ZS-EPMC128098994154045110.1186/s13045-025-01777-0