MLX, also known as Max-like protein X, is a key component in the Myc-MLX network. It acts as a heterodimer binding partner for glucose-sensing transcription factors. MLX is involved in various metabolic pathways, such as lipid and glucose metabolism, and plays a role in maintaining redox balance. It is also associated with processes like sugar sensing and the Golgi stress response, highlighting its overall biological importance. Genetic models, especially KO mouse models, have been crucial in studying its functions [1,2,3,4,5,6,7,8,9].

In osteosarcoma, knockdown of MLX impairs tumor growth and metastasis, and disturbs iron transport and storage, leading to ferroptosis. MLX regulates SLC7A11 to maintain redox balance [1]. In primary human hepatocytes, MLX knockdown alters lipid and glucose metabolism, favoring lipid catabolism over anabolism and increasing glucose production [2]. In HCC, liver-specific knockout of Mlx decreases lipogenic gene expression, lipid levels, and blocks tumor development in multiple HCC models [3]. Body-wide Mlx inactivation in mice accelerates aging-related phenotypes and deregulation of aging-related Myc target gene sets [4].

In conclusion, MLX is essential in regulating multiple metabolic processes and redox balance. Studies using KO/CKO mouse models have revealed its significance in diseases like osteosarcoma, non-alcoholic fatty liver disease-related conditions, and hepatocellular carcinoma. These findings provide insights into potential therapeutic targets for these diseases.

References:

1. Guo, Weitang, Wang, Xin, Lu, Bing, Zhao, Wei, Zou, Changye. 2023. Super-enhancer-driven MLX mediates redox balance maintenance via SLC7A11 in osteosarcoma. In Cell death & disease, 14, 439. doi:10.1038/s41419-023-05966-y. https://pubmed.ncbi.nlm.nih.gov/37460542/

2. Nagarajan, Shilpa R, Livingstone, Eilidh J, Monfeuga, Thomas, Ruby, Maxwell A, Hodson, Leanne. 2023. MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies. In Metabolism: clinical and experimental, 144, 155563. doi:10.1016/j.metabol.2023.155563. https://pubmed.ncbi.nlm.nih.gov/37088121/

3. Yu, Aijuan, Yu, Pengcheng, Zhu, Yuwen, Ye, Dan, Yu, Fa-Xing. 2023. Glucose-induced and ChREBP: MLX-mediated lipogenic program promotes hepatocellular carcinoma development. In Oncogene, 42, 3182-3193. doi:10.1038/s41388-023-02831-2. https://pubmed.ncbi.nlm.nih.gov/37684408/

4. Wang, Huabo, Stevens, Taylor, Lu, Jie, Vockley, Jerry, Prochownik, Edward V. 2023. The Myc-Like Mlx Network Impacts Aging and Metabolism. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.11.26.568749. https://pubmed.ncbi.nlm.nih.gov/38076995/

5. Billin, A N, Ayer, D E. . The Mlx network: evidence for a parallel Max-like transcriptional network that regulates energy metabolism. In Current topics in microbiology and immunology, 302, 255-78. doi:. https://pubmed.ncbi.nlm.nih.gov/16620032/

6. Havula, Essi, Hietakangas, Ville. 2017. Sugar sensing by ChREBP/Mondo-Mlx-new insight into downstream regulatory networks and integration of nutrient-derived signals. In Current opinion in cell biology, 51, 89-96. doi:10.1016/j.ceb.2017.12.007. https://pubmed.ncbi.nlm.nih.gov/29278834/

7. Cadena Del Castillo, Carla E, Deniz, Onur, van Geest, Femke, Hietakangas, Ville, Shimobayashi, Mitsugu. 2024. MLX phosphorylation stabilizes the ChREBP-MLX heterotetramer on tandem E-boxes to control carbohydrate and lipid metabolism. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.09.04.611172. https://pubmed.ncbi.nlm.nih.gov/39282306/

8. Havula, Essi, Hietakangas, Ville. 2012. Glucose sensing by ChREBP/MondoA-Mlx transcription factors. In Seminars in cell & developmental biology, 23, 640-7. doi:10.1016/j.semcdb.2012.02.007. https://pubmed.ncbi.nlm.nih.gov/22406740/

9. Taniguchi, Mai, Sasaki-Osugi, Kanae, Oku, Masaya, Wakabayashi, Sadao, Yoshida, Hiderou. 2016. MLX Is a Transcriptional Repressor of the Mammalian Golgi Stress Response. In Cell structure and function, 41, 93-104. doi:10.1247/csf.16005. https://pubmed.ncbi.nlm.nih.gov/27251850/