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. 2025 Dec 1:240:717-734.
doi: 10.1016/j.freeradbiomed.2025.09.002. Epub 2025 Sep 4.

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

Yupeng Zhao  1 , Wentao Liu  2 , Kaiyuan Deng  3 , Yunqin Chen  4 , Peng Zhou  3 , Congxing Liu  5 , Guangqing Jiang  5 , Junjie Wu  5 , Yihong Zhang  5 , Huiheng Qu  3 , Bingya Liu  6 , Beiqin Yu  7 , Xin Shi  8 , Jiazeng Xia  9
Affiliations

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

Yupeng Zhao et al. Free Radic Biol Med. .

Abstract

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.

Keywords: Gastric cancer; H3K14la; Lactylation; Oxaliplatin resistance; PCBP2.

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Conflict of interest statement

Declaration of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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