新的证据表明，KRAS 突变结直肠癌 (CRC) 的生存和进展依赖于谷氨酰胺 (Gln)，这表明针对 Gln 代谢可能是 KRAS 突变结直肠癌的一种有前景的治疗策略。然而，Gln 代谢重编程促进和协调 KRAS 突变 CRC 进展的精确机制仍有待充分研究。在这里，我们发现溶质载体 25 成员 21 (SLC25A21) 表达在 KRAS 突变 CRC 中下调，并且 SLC25A21 下调与 KRAS 突变 CRC 患者的较差生存率相关。 SLC25A21耗竭选择性地加速KRAS突变CRC细胞在体外和体内的生长、侵袭、迁移和转移，并抑制Gln衍生的α-酮戊二酸（α-KG）从线粒体流出，从而增强Gln补充，同时增加GTP 可用于 KRAS 突变 CRC 中持续激活 KRAS。 SLC25A21表达的恢复削弱了KRAS突变CRC中KRAS突变介导的西妥昔单抗耐药性。此外，因 SLC25A21 耗竭而发生的 α-KG 外流抑制抑制了 α-KG 依赖性 DNA 去甲基酶的活性，导致 SLC25A21 表达进一步下降。我们的研究表明，SLC25A21 通过拮抗 Gln 依赖性回补来限制 KRAS 激活的 GTP 可用性，从而在 KRAS 突变 CRC 中发挥重要的抑癌作用，这为 KRAS 突变 CRC 提供了潜在的替代治疗策略。

Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.