膀胱癌（BCa）是全球第四常见的恶性肿瘤，预后不良。需要进一步探索和研究来揭示环状RNA的潜在作用和分子机制。在本研究中，我们的发现显示，circXRN2通过激活Hippo通路，抑制组蛋白乳酸化驱动的人膀胱癌肿瘤进展。RNA免疫沉淀（RIP）结合环状RNA测序确认circXRN2作为研究对象。在T24和TCCSUP细胞中，circXRN2过表达和TAZ/YAP沉默验证了其在生物学功能中的作用。使用RIP、免疫沉淀和共免疫沉淀来阐明circXRN2和LATS1之间的相互作用。使用Seahorse代谢分析仪确定糖酵解速率。利用Cleavage under targets and Tagmentation（CUT&Tag）和染色质免疫沉淀（ChIP）确定H3K18乳酸化在LCN2转录活性中的调控作用。在膀胱癌组织和细胞系中，circXRN2异常下调。circXRN2抑制肿瘤细胞的增殖和迁移，无论在体外还是在体内。此外，circXRN2作为糖酵解和乳酸产生的负调控因子。从机制上说，circXRN2通过与SPOP降解基元结合来阻止LATS1的SPOP介导降解，然后激活Hippo信号通路发挥多种生物学功能。circXRN2-Hippo通路调节轴通过抑制H3K18乳酸化和LCN2在人膀胱癌中的表达，进一步调节肿瘤进展。circXRN2通过激活H3K18乳酸化驱动的Hippo信号通路，抑制人膀胱癌的肿瘤进展。我们的结果为人膀胱癌的临床干预提供了新的治疗靶点和有希望的策略。© 2023. BioMed Central Ltd., part of Springer Nature.

Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression driven by histone lactylation by activating the Hippo pathway in human bladder cancer.RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP cells. RIP, immunoprecipitation and coimmunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. A Seahorse metabolic analyzer was used to determine the glycolytic rate. Cleavage under targets and Tagmentation (CUT&Tag) and chromatin immunoprecipitation (ChIP) were employed to ensure the regulatory roles of H3K18 lactylation in the transcriptional activity of LCN2.CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits the proliferation and migration of tumor cells both in vitro and in vivo. In addition, circXRN2 serves as a negative regulator of glycolysis and lactate production. Mechanistically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP degron and then activates the Hippo signaling pathway to exert various biological functions. The circXRN2-Hippo pathway regulatory axis further modulates tumor progression by inhibiting H3K18 lactylation and LCN2 expression in human bladder cancer.CircXRN2 suppresses tumor progression driven by H3K18 lactylation by activating the Hippo signaling pathway in human bladder cancer. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer.© 2023. BioMed Central Ltd., part of Springer Nature.