LncRNA BASP1-AS1 drives PCBP2 K115 lactylation to suppress ferroptosis and confer oxaliplatin resistance in gastric cancer.

In oxaliplatin-resistant gastric cancer (GC), multi-omics profiling combined with organoid libraries reveals altered metabolic pathways associated with chemoresistance. We identify a novel lactylation modification at K115 of Poly(RC)-binding protein 2 (PCBP2K115la), which confers functional oxaliplatin resistance. Mechanistic studies demonstrate that the long non-coding RNA BASP1-AS1 assembles a complex containing Unc-51 Like Autophagy Activating Kinase 1 (ULK1) and lactate dehydrogenase A (LDHA), thereby activating LDHA enzymatic activity to increase lactate production. Elevated lactate triggers PCBP2K115la modification, disrupting PCBP2-ARIH2 interaction to inhibit ubiquitin-dependent degradation and stabilize PCBP2. Concurrently, BASP1-AS1-mediated histone H3K14 lactylation transcriptionally upregulates both LDHA and PCBP2, generating a self-amplifying metabolic-epigenetic circuit. This axis critically suppresses ferroptosis and maintains chemoresistance, providing actionable targets for overcoming oxaliplatin resistance in GC.