Scd1, short for stearoyl-CoA desaturase 1, is a key enzyme in lipid metabolism. It desaturates saturated fatty acids (SFAs) from de novo lipogenesis or diet to generate monounsaturated fatty acids (MUFAs), thus maintaining metabolic and tissue homeostasis. SCD1 is involved in multiple pathways such as AMPK/ACC, SIRT1/PGC1α, and NcDase/Wnt, and critically regulates physiological processes like energy homeostasis, development, autophagy, tumorigenesis, and inflammation [4]. Genetic models, like KO/CKO mouse models, can be valuable for studying its functions.

In cancer, SCD1 promotes cell proliferation and metastasis. In ascites-derived ovarian cancer cells, SCD1 is aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness, while its inhibition retards tumor growth, CSC formation, and reduces platinum resistance [1]. In gastric cancer, ADAR1-mediated RNA editing of SCD1 increases its mRNA stability, facilitating lipid droplet formation to alleviate chemotherapy-induced ER stress and enhancing self-renewal, and SCD1 inhibition abrogates chemoresistance [2]. In hepatocellular carcinoma, an SCD1-dependent mechanoresponsive pathway promotes invasion and metastasis in response to high matrix stiffness [3]. In colorectal cancer, TIGAR drives ferroptosis resistance via the ROS/AMPK/SCD1 pathway, and knockdown of SCD1-related genes enhances sensitivity to ferroptosis [6,5]. Also, SCD1 inhibitor enhances antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells, and synergizes with anti-PD-1 antibody [7].

In conclusion, Scd1 is crucial in lipid metabolism and significantly impacts various biological processes. Model-based research, especially KO/CKO mouse models, has revealed its role in promoting tumorigenesis and metastasis in multiple cancers, highlighting its potential as a therapeutic target in cancer treatment. It also plays a role in processes related to ferroptosis and the tumor immune response, further emphasizing its importance in understanding disease mechanisms.

References:

1. Xuan, Yang, Wang, Huogang, Yung, Mingo Mh, Chan, Karen Kl, Chan, David W. 2022. SCD1/FADS2 fatty acid desaturases equipoise lipid metabolic activity and redox-driven ferroptosis in ascites-derived ovarian cancer cells. In Theranostics, 12, 3534-3552. doi:10.7150/thno.70194. https://pubmed.ncbi.nlm.nih.gov/35547771/

2. Wong, Tin-Lok, Loh, Jia-Jian, Lu, Shixun, Leung, Suet Yi, Ma, Stephanie. 2023. ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer. In Nature communications, 14, 2861. doi:10.1038/s41467-023-38581-8. https://pubmed.ncbi.nlm.nih.gov/37208334/

3. Liu, Hua-Hua, Xu, Yang, Li, Cao-Jie, Ren, Zheng-Gang, Chen, Rong-Xin. 2022. An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming. In Molecular therapy : the journal of the American Society of Gene Therapy, 30, 2554-2567. doi:10.1016/j.ymthe.2022.03.015. https://pubmed.ncbi.nlm.nih.gov/35358687/

4. Sun, Qin, Xing, Xiaorui, Wang, Huanyu, Wang, Yibing, Wang, Ru. 2023. SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 170, 115586. doi:10.1016/j.biopha.2023.115586. https://pubmed.ncbi.nlm.nih.gov/38042113/

5. Chen, Hao, Qi, Qinqin, Wu, Nan, Jin, Rong, Jiang, Lei. 2022. Aspirin promotes RSL3-induced ferroptosis by suppressing mTOR/SREBP-1/SCD1-mediated lipogenesis in PIK3CA-mutant colorectal cancer. In Redox biology, 55, 102426. doi:10.1016/j.redox.2022.102426. https://pubmed.ncbi.nlm.nih.gov/35963119/

6. Liu, Min-Yao, Li, Hong-Ming, Wang, Xin-Yu, Wang, Miao, Zhang, Hong-Sheng. 2022. TIGAR drives colorectal cancer ferroptosis resistance through ROS/AMPK/SCD1 pathway. In Free radical biology & medicine, 182, 219-231. doi:10.1016/j.freeradbiomed.2022.03.002. https://pubmed.ncbi.nlm.nih.gov/35271998/

7. Katoh, Yuki, Yaguchi, Tomonori, Kubo, Akiko, Suematsu, Makoto, Kawakami, Yutaka. . Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. In Journal for immunotherapy of cancer, 10, . doi:10.1136/jitc-2022-004616. https://pubmed.ncbi.nlm.nih.gov/35793868/