浙江大学闵军霞等研究人员合作揭示了SLC7A11介导的非必需氨基酸在MASLD中的重要性。相关论文于2024年9月19日在线发表于国际学术期刊《科学通报》。

研究人员发现非必需氨基酸（NEAA）转运蛋白SLC7A11，在代谢功能障碍相关脂肪性肝病（MASLD）中起关键作用。在MASLD患者中，SLC7A11的高表达水平与临床分级直接相关。

通过功能缺失和功能获得的基因模型研究，研究人员发现，Slc7a11缺陷通过经典的半胱氨酸/胱氨酸缺乏诱导的铁死亡加速了MASLD的进展，而在肝脏中过表达Slc7a11的小鼠中，丝氨酸缺乏及其导致的体内半胱氨酸合成障碍，被认为是铁死亡诱导MASLD进展的原因。

与这些发现一致的是，丝氨酸补充和阻断铁死亡显著缓解了MASLD，并且在这些前临床疾病模型中，血清丝氨酸/谷氨酸比率显著降低，表明其可能成为MASLD患者的预后生物标志物。这些研究结果表明，非必需氨基酸代谢缺陷参与了MASLD的进展，丝氨酸缺乏触发的铁死亡可能为其治疗提供了一个潜在的靶点。

据悉，MASLD已成为全球健康负担迅速增加的疾病。

附：英文原文

Title: Essentiality of SLC7A11-mediated nonessential amino acids in MASLD

Author: Fudi Wang b c d, Junxia Min a

Issue&Volume: 2024/09/19

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) remains a rapidly growing global health burden. Here, we report that the nonessential amino acid (NEAA) transporter SLC7A11 plays a key role in MASLD. In patients with MASLD, we found high expression levels of SLC7A11 that were correlated directly with clinical grade. Using both loss-of-function and gain-of-function genetic models, we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiency-induced ferroptosis, while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11. Consistent with these findings, we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD, and the serum serine/glutamate ratio was significantly lower in these preclinical disease models, suggesting that it might serve as a prognostic biomarker for MASLD in patients. These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.

DOI: 10.1016/j.scib.2024.09.019

Source: https://www.sciencedirect.com/science/article/pii/S2095927324006698