Talaroconvolutin-A (TalaA) 是中草药三七 (Panax notoginseng) 内生真菌 T. convolutispora 的化合物。 TalaA 是否在膀胱癌中发挥抗癌活性仍不清楚。我们从转录组、蛋白质组、磷酸蛋白质组和分子相互作用的角度探索了 TalaA 的抗癌功能并研究了 TalaA 的药理机制。使用 CCK8 测定、EdU 染色、结晶紫染色、流式细胞术、活/死细胞染色和蛋白质印迹，我们研究了 TalaA 的体外抗癌活性。对于体内分析，我们进行了异种移植肿瘤植入。通过苏木精和伊红评价 TalaA 的抗肿瘤作用（H

Talaroconvolutin-A (TalaA) is a compound from the endophytic fungus T. convolutispora of the Chinese herbal medicine Panax notoginseng. Whether TalaA exerts anticancer activity in bladder cancer remains unknown. We explored anticancer function and studied the pharmacological mechanism of TalaA from transcriptomic, proteomic, phosphoproteomic, and molecular interaction perspectives. Using CCK8 assay, EdU staining, crystal violet staining, flow cytometry, living/dead cell staining, and western blotting we studied the anticancer activity of TalaA in vitro. For in vivo analysis, we performed xenograft tumor implantation. The anti-tumor effects of TalaA were evaluated through hematoxylin and eosin (H&E) and immunohistochemistry staining and pathological analysis. In high-throughput omics detection, proteomics was conducted to detect changes in the protein profile; transcriptomics was performed used to detect changes in mRNA abundance; phosphoproteomics was used to detect changes in protein phosphorylation. We found TalaA inhibited tumor cell proliferation, DNA replication, and colony formation in a dose-dependent manner in bladder cancer cells. The IC50 values of TalaA on SW780 and UM-UC-3 cells were 5.7 and 8.2 μM respectively. TalaA (6.0 mg/kg) significantly repressed the growth of xenografted tumors and did not affect the body weight nor cause obvious hepatorenal toxicity. In pharmacological mechanism, TalaA arrested the cell cycle by downregulating cyclinA2, cyclinB1, and AURKB and upregulating p21/CIP. TalaA also elevated intracellular reactive oxygen species and upregulated transferrin (TF) and heme oxygenase 1 (HMOX1) to induce ferroptosis. Moreover, TalaA was able to bind to MAPKs (MAPK1, MAPK8, and MAPK14) to inhibit the phosphorylation of *SP* motif sites of transcription regulators. This study revealed that TalaA inhibited bladder cancer mainly by arresting cell cycle to suppress proliferation and triggering ferroptosis to cause cell death. Conclusively, TalaA would be a potential candidate for treating bladder cancer by targeting MAPKs, suppressing the cell cycle, and inducing ferroptosis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.