Slc16a4, also known as monocarboxylate transporter 4 (MCT4), is a key transporter for lactate. It is involved in maintaining intracellular pH homeostasis and plays a crucial role in the lactate-related metabolic pathways. Lactate, produced by glycolytic cells, is transported across cell membranes by MCT4, and this process is important for energy metabolism, cell-cell communication, and immune regulation in various biological systems [3].

In LKB1-deficient lung adenocarcinoma, MCT4-dependent lactate secretion suppresses antitumor immunity. MCT4 knockout in syngeneic murine models reverses the resistance to PD-1 blockade induced by LKB1 loss, indicating its role in immunotherapy resistance [1]. In the context of cardiac hypertrophy and heart failure, genetic ablation of the mitochondrial pyruvate carrier leads to increased MCT4-mediated lactate export, and a novel MCT4 inhibitor mitigates hypertrophy in cultured cardiomyocytes and mice [2]. In macrophage-related atherosclerosis, MCT4-mediated histone lactylation is closely related to the disease. MCT4 deficiency activates anti-inflammatory genes and tricarboxylic acid cycle genes, favoring the amelioration of atherosclerosis [4]. In hepatocellular carcinoma, genetic or pharmacological inhibition of MCT4 using VB124 suppresses tumor growth by enhancing CD8+ T cell infiltration and cytotoxicity in immunocompetent mice [5]. In type 2 diabetes-related cardiomyopathy, MCT4-dependent lactate transport leads to oxidative stress, inflammation, and myocardial damage in cardiomyocytes, and inhibiting MCT4 alleviates these issues in type 2 diabetic mice [6].

In conclusion, Slc16a4 (MCT4) is essential for lactate-related physiological and pathological processes. Gene knockout studies in mouse models have revealed its significance in multiple disease areas, including cancer immunotherapy resistance, cardiac diseases, atherosclerosis, and type 2 diabetes-related cardiomyopathy. Understanding the role of Slc16a4 through these models provides valuable insights into the underlying mechanisms of these diseases and potential therapeutic strategies.

References:

1. Qian, Yu, Galan-Cobo, Ana, Guijarro, Irene, Reuben, Alexandre, Heymach, John V. 2023. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. In Cancer cell, 41, 1363-1380.e7. doi:10.1016/j.ccell.2023.05.015. https://pubmed.ncbi.nlm.nih.gov/37327788/

2. Cluntun, Ahmad A, Badolia, Rachit, Lettlova, Sandra, Rutter, Jared, Drakos, Stavros G. 2020. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. In Cell metabolism, 33, 629-648.e10. doi:10.1016/j.cmet.2020.12.003. https://pubmed.ncbi.nlm.nih.gov/33333007/

3. Payen, Valéry L, Mina, Erica, Van Hée, Vincent F, Porporato, Paolo E, Sonveaux, Pierre. 2019. Monocarboxylate transporters in cancer. In Molecular metabolism, 33, 48-66. doi:10.1016/j.molmet.2019.07.006. https://pubmed.ncbi.nlm.nih.gov/31395464/

4. Zhang, Yunjia, Jiang, Hong, Dong, Mengdie, Li, Xuesong, Chen, Hongshan. 2024. Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation. In Cell reports, 43, 114180. doi:10.1016/j.celrep.2024.114180. https://pubmed.ncbi.nlm.nih.gov/38733581/

5. Fang, Yuan, Liu, Weiren, Tang, Zheng, Xu, Wei, Shi, Yinghong. 2022. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. In Hepatology (Baltimore, Md.), 77, 109-123. doi:10.1002/hep.32348. https://pubmed.ncbi.nlm.nih.gov/35043976/

6. Ma, Xiu Mei, Geng, Kang, Wang, Peng, Law, Betty Yuen-Kwan, Xu, Yong. 2024. MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus. In Cardiovascular diabetology, 23, 96. doi:10.1186/s12933-024-02178-2. https://pubmed.ncbi.nlm.nih.gov/38486199/