AKR1B1, also known as aldose reductase, is an NADPH-dependent cytosolic enzyme that catalyzes the conversion of excess glucose to sorbitol as part of the polyol pathway. This pathway is involved in the energy metabolism of plasm glucose and ROS production, and AKR1B1 has been associated with various biological processes including cell differentiation, proliferation, and apoptosis [4].

In leukemia, SMARCA5 promotes transcriptional activation of AKR1B1, which is associated with a poor prognosis. Pharmacological inhibition of AKR1B1 has significant therapeutic effects in leukemia mice and patient cells, suggesting its role in leukemogenesis [1]. In lung cancer, AKR1B1 interacts with and activates STAT3 to up-regulate SLC7A11, leading to EGFR TKI drug resistance. Suppression of AKR1B1 restores drug sensitivity [2]. In cancer cells, deletion of AKR1B1 suppresses glycolysis, migration, growth, and induces apoptosis and cell cycle arrest, highlighting its role in cancer cell malignancy [3].

In summary, AKR1B1 plays crucial roles in multiple disease conditions, especially in cancer-related processes such as metabolism reprogramming, drug resistance, and cell malignancy. The findings from studies on AKR1B1, including those using potential functional models like gene-targeted mouse models (although not explicitly detailed in the references regarding KO/CKO mouse models), contribute to understanding the biological functions of this gene and may provide therapeutic strategies for leukemia, lung cancer, and other related diseases.

References:

1. Yu, Peng-Cheng, Hou, Dan, Chang, Binhe, Sun, Xiao-Jian, Wang, Lan. 2024. SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis. In Developmental cell, 59, 1954-1971.e7. doi:10.1016/j.devcel.2024.04.023. https://pubmed.ncbi.nlm.nih.gov/38776924/

2. Zhang, Ke-Ren, Zhang, Yu-Fei, Lei, Hui-Min, Chen, Hong-Zhuan, Zhu, Liang. 2021. Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer. In Science translational medicine, 13, eabg6428. doi:10.1126/scitranslmed.abg6428. https://pubmed.ncbi.nlm.nih.gov/34613810/

3. Zhao, Qing, Han, Bing, Wang, Lu, Chen, Wen-Lian, Jia, Wei. 2024. AKR1B1-dependent fructose metabolism enhances malignancy of cancer cells. In Cell death and differentiation, 31, 1611-1624. doi:10.1038/s41418-024-01393-4. https://pubmed.ncbi.nlm.nih.gov/39406918/

4. Banerjee, Sreeparna. . Aldo Keto Reductases AKR1B1 and AKR1B10 in Cancer: Molecular Mechanisms and Signaling Networks. In Advances in experimental medicine and biology, 1347, 65-82. doi:10.1007/5584_2021_634. https://pubmed.ncbi.nlm.nih.gov/33945128/