Bladder cancer (BC) is significantly more prevalent in men than in women, yet female patients often experience higher recurrence rates and poorer prognosis.

Our study aimed to investigate sex-specific gene expression differences in early-stage BC using whole-transcriptome sequencing. A total of 51 patients diagnosed with low-grade Ta stage non-muscle-invasive bladder cancer were recruited. Paired tissue samples from tumor lesions and adjacent healthy bladder mucosa (BM) were analyzed to identify differentially expressed genes (DEGs).

Among the top 100 most significant DEGs for each gender, overwhelmingly more upregulated in BC comparing with BM were in male than female tissues (90% vs. 19%). The most significantly altered expression in female BC tissues included MT-ND6, ARL4C, ASGR1, MYBL1, and SCAMP5, whereas in males, ONECUT2, SPEG, CTSE, GJB2, and SYNM. Notably, 753 DEGs were unique to female patients, while 3989 were specific to males, with 1633 shared between both sexes. Functional annotation revealed that female-unique DEGs were significantly enriched in immune-related pathways, including regulation of leukocyte activation and cell–cell adhesion, and lymphocyte differentiation. Whereas male-unique DEGs were predominantly associated with pathways related to cell cycle regulation, mitochondrial function, and androgen receptor signaling. Immune-related gene expression indicated that female-specific DEGs were involved in leukocyte activation and antigen receptor signaling, whereas male-specific DEGs were linked to B-cell activation and neutrophil-mediated immune responses. A two-factor interaction model identified S100A14 as the only protein-coding gene whose expression exhibited a significant sex-dependent pattern, with four additional genes (GJB2, DSC2, TM4SF and ALOX15B) showing a probable interaction effect.

These findings provide preliminary evidence supporting further investigation of sex-specific approaches to BC management.