前列腺癌（PCa）是男性成年人中最常见的实体肿瘤之一。然而，大多数抗血管生成治疗和免疫治疗在晚期前列腺癌中无法实现持久缓解。综合分析表明，Sema3A与病理恶性程度呈负相关，并参与了前列腺癌的血管生成、细胞粘附和免疫浸润。Sema3A显著抑制血管内皮生长因子（VEGFA）诱导的前列腺癌细胞的集落形成、细胞增殖和PD-L1的表达。网络药理学分析表明，Evodiae fructus果实中提取的天然生物碱化合物马钱子碱可能调节前列腺癌的Sema3A、脂质代谢和单羧酸转运信号。马钱子碱明显以时间剂量依赖的方式抑制前列腺癌细胞的存活能力。此外，马钱子碱通过增加Sema3A的表达抑制了血管生成，并通过减少谷胱甘肽过氧化物酶4（GPX4）的表达诱导了铁过氧化物死亡，而这可以通过铁过氧化物死亡阻断剂铁过氧化物死亡阻断剂1来逆转。乳酸处理增加了低氧诱导因子（HIF）-1α和PD-L1的表达，同时限制了前列腺癌细胞中Sema3A的表达，这可以通过沉默单羧酸转运体4（MCT4）表达来逆转。此外，马钱子碱通过限制组蛋白乳酸化和HIF1A表达，明显阻断了乳酸诱导的血管生成，并进一步增强了前列腺癌细胞中的Sema3A转录，同时抑制了PD-L1的转录。在体内，马钱子碱显著抑制了裸鼠中前列腺癌异种移植物的生长，抑制了HIF1α、H3K18la、GPX4、PD-L1和增殖的表达，同时通过增加Sema3A的表达抑制了血管生成。因此，Sema3A是一个重要的抗肿瘤生物标志物，马钱子碱可能起到代谢表观遗传调节剂的作用，并且可能是前列腺癌抗血管生成治疗或免疫治疗的有前途的药物。版权所有 © 2023 Elsevier B.V. 发布。

Prostate cancer (PCa) is among the most commonly diagnosed solid cancers in male adults. However, most anti-angiogenic therapies and immunotherapies fail to achieve durable remission in advanced PCa. Integrative analysis indicated that Sema3A was negatively correlated with the pathological malignancy and was involved in angiogenesis, cell adhesion, and immune infiltrates in PCa. Sema3A significantly inhibited vascular endothelial growth factor (VEGFA)-induced colony formation, cell proliferation, and PD-L1 expression in PCa cells. Network pharmacological analysis demonstrated that evodiamine, a natural alkaloid compound derived from Evodiae fructus fruits, might regulate Sema3A, lipid metabolism, and monocarboxylic acid transport signaling of PCa. Evodiamine evidently inhibited PCa cell viability in a time-dose-dependent manner. Furthermore, evodiamine impaired angiogenesis by increasing Sema3A expression, and induced ferroptosis by reducing glutathione peroxidase 4 (GPX4) expression, which could be reversed by the ferroptosis blocker ferrostatin-1. Lactate treatment increased hypoxia-inducible factor (HIF)-1α and PD-L1 expressions while restricting Sema3A expression in PCa cells, which could be reversed by silencing monocarboxylate transporter 4 (MCT4) expression. Moreover, evodiamine markedly blocked lactate-induced angiogenesis by restricting histone lactylation and expression of HIF1A in PCa cells, further enhancing Sema3A transcription while inhibiting that of PD-L1. In vivo, evodiamine remarkably inhibited PCa xenograft growth in nude mice, repressing expressions of HIF1α, H3K18la, GPX4, PD-L1, and proliferation, while hindering angiogenesis by increasing Sema3A expression. Therefore, Sema3A represents an essential antineoplastic biomarker, while evodiamine may act as a metabolic-epigenetic modulator, as well as a promising agent in either PCa anti-angiogenic therapy or immunotherapy.Copyright © 2023. Published by Elsevier B.V.