Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Brusatol inhibits gastric cancer by targeting P4HA2 and supressing glycolysis-driven histone lactylation.
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Zhang Kaiyuan, Ni Xiaochen, Wang Chuhang, Guo Jianing, Fan Wei, Jiang Tao, Zhang Guangji
Аннотация
BACKGROUND: Brusatol (BRU) is a bioactive derived from Brucea javanica. It has demonstrated anti-tumor effects in gastric cancer (GC). However, its role in regulating metabolic-epigenetic cross-talk remains poorly understood.
PURPOSE: This study aimed to elucidate how BRU inhibits GC progression by modulating metabolic reprogramming and histone lactylation.
METHODS: We treated GC cell lines (AGS and MKN45) and xenograft models with BRU. Our methodology combined multi-omics analysis, molecular docking, CETSA, metabolic assays, and CUT&Tag sequencing. We used functional validation through prolyl-4-hydroxylase subunit alpha-2 (P4HA2) overexpression and lactate rescue experiments.
RESULTS: BRU selectively inhibited GC proliferation with minimal toxicity to normal gastric cells. Using multi-omics approaches, we found that BRU treatment markedly suppressed glycolysis, as evidenced by the downregulation of key enzymes. Integrated omics identified P4HA2 as a key target, which BRU bound directly and promoted its lysosomal degradation. P4HA2 suppression downregulated glycolytic enzymes, reducing lactate production. Consequently, BRU decreased histone H3K9lac/H3K18lac modifications by inhibiting the lactylation "writer" HBO1. CUT&Tag results showed that BRU lowered H3K18lac occupancy at gene promoters. This lactylation decline suppressed transcription of the mitotic regulator TTK. In vivo, BRU suppressed tumor growth and reduced Ki-67, PCNA, LDHA, Pan-Kla, H3K9lac, and H3K18lac levels.
CONCLUSION: BRU inhibites GC progression by targeting P4HA2, disrupting glycolysis-histone lactylation signaling, and downregulating TTK. This metabolic-epigenetic mechanism positions BRU as a promising natural therapeutic for GC.
PURPOSE: This study aimed to elucidate how BRU inhibits GC progression by modulating metabolic reprogramming and histone lactylation.
METHODS: We treated GC cell lines (AGS and MKN45) and xenograft models with BRU. Our methodology combined multi-omics analysis, molecular docking, CETSA, metabolic assays, and CUT&Tag sequencing. We used functional validation through prolyl-4-hydroxylase subunit alpha-2 (P4HA2) overexpression and lactate rescue experiments.
RESULTS: BRU selectively inhibited GC proliferation with minimal toxicity to normal gastric cells. Using multi-omics approaches, we found that BRU treatment markedly suppressed glycolysis, as evidenced by the downregulation of key enzymes. Integrated omics identified P4HA2 as a key target, which BRU bound directly and promoted its lysosomal degradation. P4HA2 suppression downregulated glycolytic enzymes, reducing lactate production. Consequently, BRU decreased histone H3K9lac/H3K18lac modifications by inhibiting the lactylation "writer" HBO1. CUT&Tag results showed that BRU lowered H3K18lac occupancy at gene promoters. This lactylation decline suppressed transcription of the mitotic regulator TTK. In vivo, BRU suppressed tumor growth and reduced Ki-67, PCNA, LDHA, Pan-Kla, H3K9lac, and H3K18lac levels.
CONCLUSION: BRU inhibites GC progression by targeting P4HA2, disrupting glycolysis-histone lactylation signaling, and downregulating TTK. This metabolic-epigenetic mechanism positions BRU as a promising natural therapeutic for GC.