Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD⁺ decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.

溶质载体家族 25 成员 51 (SLC25A51) 最近被鉴定为对线粒体功能至关重要的哺乳动物线粒体 NAD+ 转运蛋白。然而，SLC25A51 在癌症等人类疾病中的作用仍不清楚。在此，我们报告 SLC25A51 在多种癌症中表达上调，从而促进癌细胞增殖。 SLC25A51 的缺失会因 SIRT3 功能障碍而升高线粒体蛋白乙酰化水平，导致脯氨酸生物合成中关键酶 P5CS 酶活性受损，并导致脯氨酸含量减少。值得注意的是，我们发现FDA批准的磷酸氟达拉滨能够结合并抑制SLC25A51功能，导致线粒体NAD ⁺减少和蛋白质过度乙酰化，这可以进一步与阿司匹林协同增强抗肿瘤功效。我们的研究表明，SLC25A51 是一个有吸引力的抗癌靶点，并提供了磷酸氟达拉滨与阿司匹林的新型药物组合作为潜在的癌症治疗策略。