Acsl3, short for acyl-CoA synthetase long-chain family member 3, is an enzyme in the long-chain fatty acyl CoA synthetase (ACSLs) family. It significantly contributes to lipid metabolism by catalyzing the production of acyl-coenzyme A from fatty acids, which is crucial for fatty acid oxidation. This process is involved in multiple biological pathways, such as lipid droplet biogenesis and ferroptosis regulation [1].

In clear cell renal cell carcinoma (ccRCC), ACSL3 is required for the metabolism of exogenous fatty acids into lipid droplets. Genetic or pharmacologic suppression of ACSL3 is cytotoxic to ccRCC cells in vitro and reduces tumor weight in an orthotopic mouse model. Also, ACSL3 inhibition decreases the susceptibility of ccRCC cells to ferroptosis [2]. In breast cancer, ACSL3 expression is downregulated in cancer tissues compared to normal tissues. Knockdown of ACSL3 in breast cancer cells promotes cell proliferation, migration, and epithelial-mesenchymal transition, indicating its role in suppressing breast cancer progression [3]. In cholangiocarcinoma, ACSL3 is upregulated in high-risk cell lines, conferring resistance to ferroptosis inducer RSL3, and its silencing sensitizes these cells to RSL3 [4].

In conclusion, ACSL3 plays essential roles in lipid metabolism-related biological processes and has significant implications in multiple cancers, including ccRCC, breast cancer, and cholangiocarcinoma. Studies using in vivo models like orthotopic mouse models in ccRCC have revealed its role in tumor growth and ferroptosis sensitivity, highlighting its potential as a therapeutic target in these diseases.

References:

1. Yang, Yufei, Zhu, Ting, Wang, Xu, Yuan, Xiao, Wang, Deqiang. 2022. ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers. In Cancers, 14, . doi:10.3390/cancers14235896. https://pubmed.ncbi.nlm.nih.gov/36497375/

2. Klasson, Timothy D, LaGory, Edward L, Zhao, Hongjuan, Moon, Eui Jung, Giaccia, Amato J. 2022. ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma. In Cancer & metabolism, 10, 14. doi:10.1186/s40170-022-00290-z. https://pubmed.ncbi.nlm.nih.gov/36192773/

3. Tan, Shirong, Sun, Xiangyu, Dong, Haoran, Xu, Ling, Xu, Yingying. . ACSL3 regulates breast cancer progression via lipid metabolism reprogramming and the YES1/YAP axis. In Cancer biology & medicine, 21, 606-35. doi:10.20892/j.issn.2095-3941.2023.0309. https://pubmed.ncbi.nlm.nih.gov/38953696/

4. Sae-Fung, Apiwit, Vinayavekhin, Nawaporn, Fadeel, Bengt, Jitkaew, Siriporn. 2024. ACSL3 is an unfavorable prognostic marker in cholangiocarcinoma patients and confers ferroptosis resistance in cholangiocarcinoma cells. In NPJ precision oncology, 8, 284. doi:10.1038/s41698-024-00783-8. https://pubmed.ncbi.nlm.nih.gov/39706856/