长链非编码RNA（lncRNA）的失调与许多人类肿瘤的发生和进展有关。乳酸脱氢酶A（LDHA）酶活性对肿瘤的发展也至关重要，包括乳头状甲状腺癌（PTC）的发展。然而，特定的lncRNA是否可以调节癌症进展中的LDHA活性仍不清楚。通过筛选，我们发现一个与LDHA相互作用的lncRNA，即GLTC，在PTC的增加的有氧糖酵解和细胞存活中是必需的。与非肿瘤甲状腺组织相比，GLTC在PTC组织中显著上调。高表达的GLTC与更广泛的远处转移、更大的肿瘤大小和更差的预后相关。质谱分析揭示了GLTC作为LDHA的结合伴侣，通过竞争性抑制SIRT5和LDHA之间的相互作用，促进LDHA在赖氨酸155（K155）位点的琥珀酰化，从而促进LDHA酶活性。琥珀酰化模拟LDHAK155E突变体的过表达恢复了代谢重编程和细胞存活在GLTC耗竭的细胞中停止的情况下。有趣的是，GLTC抑制消除了K155-琥珀酰化的LDHA对放射碘（RAI）抗性的影响，无论在体外还是体内。综上所述，我们的结果表明，GLTC发挥了肿瘤原性作用，是PTC治疗中RAI敏感化的有吸引力的靶点。©2023年。作者（们）授予ADMC分化和细胞死亡协会独家许可。

Dysregulation of long noncoding RNAs (lncRNAs) has been associated with the development and progression of many human cancers. Lactate dehydrogenase A (LDHA) enzymatic activity is also crucial for cancer development, including the development of papillary thyroid cancer (PTC). However, whether specific lncRNAs can regulate LDHA activity during cancer progression remains unclear. Through screening, we identified an LDHA-interacting lncRNA, GLTC, which is required for the increased aerobic glycolysis and cell viability in PTC. GLTC was significantly upregulated in PTC tissues compared with nontumour thyroid tissues. High expression of GLTC was correlated with more extensive distant metastasis, a larger tumour size, and poorer prognosis. Mass spectrometry revealed that GLTC, as a binding partner of LDHA, promotes the succinylation of LDHA at lysine 155 (K155) via competitive inhibition of the interaction between SIRT5 and LDHA, thereby promoting LDHA enzymatic activity. Overexpression of the succinylation mimetic LDHAK155E mutant restored glycolytic metabolism and cell viability in cells in which metabolic reprogramming and cell viability were ceased due to GLTC depletion. Interestingly, GLTC inhibition abrogated the effects of K155-succinylated LDHA on radioiodine (RAI) resistance in vitro and in vivo. Taken together, our results indicate that GLTC plays an oncogenic role and is an attractive target for RAI sensitisation in PTC treatment.© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.