CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression Prostate cancer (PCa) is a common malignancy in men, but the molecular mechanisms of its pathogenesis remain unclear. This study demonstrates that CYLD, a deubiquitinating enzyme, suppresses PCa development and progression by inhibiting tumor cell proliferation and enhancing sensitivity to ferroptosis. CYLD suppresses YAP ubiquitination, promoting ACSL4 and TFRC mRNA transcription, which enhances ferroptosis sensitivity in PCa cells. CYLD expression is inversely correlated with PCa pathological grade and clinical stage, and is positively correlated with ACSL4 and TFRC expression in human PCa specimens. CYLD acts as a tumor suppressor gene in PCa, promoting ferroptosis through Hippo/YAP signaling. CYLD knockdown increases cell proliferation and reduces ferroptosis sensitivity, while CYLD overexpression decreases cell proliferation and increases ferroptosis sensitivity. CYLD interacts with and stabilizes YAP protein by deubiquitination, which activates ACSL4 and TFRC expression, promoting ferroptosis. CYLD overexpression inhibits Hippo signaling pathway activation and stabilizes YAP protein, enhancing ferroptosis in PCa cells. CYLD expression is lower in PCa tissues compared to normal prostate tissues, and gene deletion is common in PCa tissues. CYLD plays an anti-oncogene role in PCa by promoting ferroptosis through Hippo/YAP signaling. These findings suggest that CYLD is a potential molecular target for PCa therapy.CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression Prostate cancer (PCa) is a common malignancy in men, but the molecular mechanisms of its pathogenesis remain unclear. This study demonstrates that CYLD, a deubiquitinating enzyme, suppresses PCa development and progression by inhibiting tumor cell proliferation and enhancing sensitivity to ferroptosis. CYLD suppresses YAP ubiquitination, promoting ACSL4 and TFRC mRNA transcription, which enhances ferroptosis sensitivity in PCa cells. CYLD expression is inversely correlated with PCa pathological grade and clinical stage, and is positively correlated with ACSL4 and TFRC expression in human PCa specimens. CYLD acts as a tumor suppressor gene in PCa, promoting ferroptosis through Hippo/YAP signaling. CYLD knockdown increases cell proliferation and reduces ferroptosis sensitivity, while CYLD overexpression decreases cell proliferation and increases ferroptosis sensitivity. CYLD interacts with and stabilizes YAP protein by deubiquitination, which activates ACSL4 and TFRC expression, promoting ferroptosis. CYLD overexpression inhibits Hippo signaling pathway activation and stabilizes YAP protein, enhancing ferroptosis in PCa cells. CYLD expression is lower in PCa tissues compared to normal prostate tissues, and gene deletion is common in PCa tissues. CYLD plays an anti-oncogene role in PCa by promoting ferroptosis through Hippo/YAP signaling. These findings suggest that CYLD is a potential molecular target for PCa therapy.