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)-1alpha 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 HIF1alpha, 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. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved.