Brusatol inhibits gastric cancer by targeting P4HA2 and supressing glycolysis-driven histone lactylation.

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.