美国纪念斯隆-凯特琳癌症中心Scott W. Lowe研究组宣布他们开发出在组织再生过程中，代谢适应直接影响细胞命运。该项研究成果发表在2025年6月11日出版的《自然》上。

本研究表明，TCA循环酶在肠道中以异质方式表达，αKG脱氢酶复合物的组分在吸收谱系中上调，在分泌谱系中下调。利用转基因小鼠模型和类器官，研究组发现2-氧戊二酸脱氢酶（OGDH）， αKG脱氢酶复合物的酶亚基，具有双重谱系特异性的作用。在吸收谱系中，OGDH通过HNF4转录因子上调，以维持肠细胞的生物能量和生物合成需求。在分泌谱系中，OGDH通过一个过程下调，当模型建立时，该过程增加αKG水平并刺激分泌细胞的分化。与此一致的是，在分泌细胞分化和成熟受损的结肠炎模型中，抑制OGDH或补充αKG可逆转这些损伤并促进组织愈合。因此，OGDH依赖性是谱系特异性的，其调控有助于指导细胞命运，为再生医学的靶向治疗提供见解。

据悉，虽然细胞命运规范通常归因于转录调控，但新出现的数据也表明与中间代谢相关的分子也起作用。例如，在三羧酸（TCA）循环中为能量生产和生物合成途径提供燃料的α-酮戊二酸（αKG）也是染色质修饰酶的辅助因子。然而，TCA循环代谢物是否在组织稳态和再生过程中调节细胞命运仍不清楚。

附：英文原文

Title: Metabolic adaptations direct cell fate during tissue regeneration

Author: Chaves-Perez, Almudena, Millman, Scott E., Janaki-Raman, Sudha, Ho, Yu-Jui, Hinterleitner, Clemens, Barthet, Valentin J. A., Morris, John P., Barriga, Francisco M., Reyes, Jose, Kyaw, Aye, Pasolli, H. Amalia, Peer, Dana, Thompson, Craig B., Finley, Lydia W. S., Cross, Justin R., Lowe, Scott W.

Issue&Volume: 2025-06-11

Abstract: Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1,2,3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4,5,6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

DOI: 10.1038/s41586-025-09097-6

Source: https://www.nature.com/articles/s41586-025-09097-6