Glycometabolic Reprogramminginduced Xrcc1 Lactylation Confers Therapeutic Resistance In Aldh1a3overexpressing Glioblastoma Guanzhang Li Di Wang You Zhai Changqing Pan Jiazheng Zhang Chen Wang Ruoyu Huang Mingchen Yu Yiming Li Xing Liu Yanwei Liu Fan Wu Zheng Zhao Huimin Hu Zhongfang Shi Ulf Dietrich Kahlert Tao Jiang Wei Zhang by Guanzhang Li & Di Wang & You Zhai & Changqing Pan & Jiazheng Zhang & Chen Wang & Ruoyu Huang & Mingchen Yu & Yiming Li & Xing Liu & Yanwei Liu & Fan Wu & Zheng Zhao & Huimin Hu & Zhongfang Shi & Ulf Dietrich Kahlert & Tao Jiang & Wei Zhang 101016/JCMET202407011 instant download after payment.

SUMMARYPatients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Understanding the mechanisms underlying such resistance in these patientsis crucial for the development of new treatments. Here, we show that the interaction between ALDH1A3and PKM2 enhances the latter’s tetramerization and promotes lactate accumulation in glioblastoma stemcells (GSCs). By scanning the lactylated proteome in lactate-accumulating GSCs, we show that XRCC1 undergoes lactylation at lysine 247 (K247). Lactylated XRCC1 shows a stronger affinity for importin a, allowingfor greater nuclear transposition of XRCC1 and enhanced DNA repair. Through high-throughput screening ofa small-molecule library, we show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventingthe ALDH1A3-mediated enhancement of PKM2 tetramerization. In vitro and in vivo treatment with D34-919 enhanced chemoradiotherapy-induced apoptosis of GBM cells. Together, our findings show thatALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response to chemoradiotherapy in ALDH1A3hi GBM.INTRODUCTIONand lipids as a source of building blocks and fuel for growth.9–11