PARP1-BCAT2 axis upregulates ABCG1 via histone lactylation to drive acquired PARP inhibitor resistance in prostate cancer

BACKGROUND: Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in prostate cancer (PCa). Although branched-chain amino acid (BCAA) metabolism is implicated in cancer biology, its specific role in PARPi resistance remains unclear. This study aims to investigate how BCAA metabolism contributes to PARPi resistance in PCa. METHODS: We compared BCAA and Branched-Chain Amino Acid Aminotransferase 2 (BCAT2) levels between PARPi-resistant and PARPi-sensitive cell lines and assessed their clinical relevance. Functional studies were conducted in vitro and in vivo using cell and mouse models. Mechanistic assays, including RNA sequencing, metabolomics, RNA-binding protein immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and Cleavage Under Targets and Tagmentation (CUT&Tag), were used to delineate BCAT2-mediated PARPi resistance. RESULTS: BCAT2 expression correlated with PARPi resistance in PCa, and increased BCAA/BCAT2 levels in PARPi-resistant tissues were associated with reduced patient survival. Mechanistically, the DNA-binding domain (DBD) of PARP1 directly bound BCAT2 mRNA and regulated its stability; PARPi-induced PARP1 trapping weakened this interaction, increased BCAT2 expression, and promoted resistance. Transcriptomic and energy-metabolism analyses indicated that BCAT2 enhanced ABCG1 transcription by augmenting glycolysis and lactate secretion, thereby increasing histone H3K18la lactylation. These findings support a PARP1-BCAT2-ABCG1 axis in PARPi resistance. Combining a BCAT2 inhibitor with PARPi produced synergistic effects in cell line-derived xenografts (CDXs) and patient-derived organoids (PDOs). CONCLUSION: The PARP1-BCAT2/H3K18la-ABCG1 axis drives PARPi resistance in PCa. Targeted BCAT2 inhibition may enhance the therapeutic efficacy of PARPi.