XYLB promotes malignant behaviors of triple-negative breast cancer via SUSD3 upregulation.

Triple-negative breast cancer (TNBC) remains a clinically challenging breast cancer subtype because of its molecular heterogeneity, early recurrence, metastatic propensity, and limited targetable drivers. Metabolic remodeling is increasingly recognized as a determinant of TNBC progression, but the contribution of pentose phosphate pathway-related enzymes to TNBC remains incompletely defined. Here, we investigated the biological role of xylulokinase (XYLB), an enzyme that converts D-xylulose to xylulose-5-phosphate (Xu5P), and its downstream mechanisms in TNBC. We found that XYLB was enriched in TNBC tissues and cell lines, and high XYLB expression was associated with unfavorable patient outcomes. Gain- and loss-of-function assays showed that XYLB promoted TNBC cell proliferation, migration, and invasion in vitro, whereas XYLB knockdown suppressed orthotopic tumor growth in vivo. Mechanistically, XYLB did not act through the canonical Xu5P-MLXIPL axis, as MLXIPL was expressed at low levels in TNBC and was negatively correlated with XYLB. Transcriptomic screening and validation identified SUSD3 as a downstream effector positively regulated by XYLB. SUSD3 knockdown impaired malignant phenotypes and partially reversed XYLB-driven proliferation, migration, and invasion. These findings identify an XYLB-SUSD3 regulatory axis in TNBC and support XYLB as a metabolism-associated biomarker and potential therapeutic entry point.