Prior studies have reported connections between cathepsins (CTS) and gynecological cancers
however, the exact causal links are yet to be fully understood. Leveraging publicly accessible genome-wide association study summary datasets, we performed a two-sample bidirectional Mendelian randomization (MR) and multivariate MR (MVMR) analysis, with the inverse variance weighted (IVW) method as the primary approach. MR analysis demonstrated inverse associations between CTSB and cervical cancer (IVW: odds ratio [OR] = 0.9995, 95% confidence interval [CI] = 0.9991-0.9999, P = .0418), CTSE and ovarian cancer (IVW: OR = 0.9197, 95% CI = 0.8505-0.9944, P = .0358), CTSZ and ovarian cancer (IVW: OR = 0.9449, 95% CI = 0.8938-0.9990, P = .0459), CTSE and high grade serous ovarian cancer (IVW: OR = 0.8939, 95% CI = 0.8248-0.9689, P = .0063), and CTSZ and high grade serous ovarian cancer (IVW: OR = 0.9269, 95% CI = 0.8667-0.9913, P = .0268). A positive correlation was identified between CTSH and clear cell ovarian cancer (IVW: OR = 1.1496, 95% CI = 1.0368-1.2745, P = .0081). Nevertheless, subsequent adjustment for the false discovery rate revealed that none of the P-values retained statistical significance (PFDR >
0.05). MVMR analysis results elucidated that CTSZ was inversely associated with cervical cancer (IVW: OR = 0.9988, 95% CI = 0.9981-0.9996, P = .0022). Moreover, a positive association was noted between CTSF and cervical cancer (IVW: OR = 1.0007, 95% CI = 1.0000-1.0014, P = .0364), and similarly, between CTSS and cervical cancer (IVW: OR = 1.0005, 95% CI = 1.0000-1.0011, P = .0490). CTSO exhibited a positive association with non-endometrioid endometrial cancer (IVW: OR = 1.4405, 95% CI = 1.1864-1.7490, P <
.001), and CTSH was positively associated with clear cell ovarian cancer (IVW: OR = 1.1167, 95% CI = 1.0131-1.2310, P = .0263). The MVMR analysis findings reveal that CTSZ emerges as a protective element against cervical cancer, whereas CTSF and CTSS represent risk factors for this disease. CTSO stands out as a risk factor for non-endometrioid endometrial cancer, and CTSH acts as a risk factor for clear cell ovarian cancer. This study elucidates causative connections between CTS and gynecological cancers, providing innovative insights for diagnostic and therapeutic optimization.