Srsf9, short for Serine/arginine-rich splicing factor 9, is a classical RNA-binding protein. It is essential for regulating gene expression programs by interacting with target RNA, and is involved in alternative splicing, a crucial post-transcriptional regulatory process [2,5]. It also plays roles in various biological processes and is associated with multiple diseases [2,3,6,9]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying Srsf9's functions.

In cardiac hypertrophy, Mettl1 upregulates Srsf9 expression through m7G modification of Srsf9 mRNA. Knockdown of Srsf9 protects against TAC-or Mettl1-induced cardiac hypertrophic phenotypes, indicating Srsf9 promotes cardiac hypertrophy [1]. In colorectal cancer, Srsf9 promotes cell proliferation, migration, and invasion. Knockdown of Srsf9 accelerates the turnover of its downstream target DSN1 mRNA, reducing CRC cell malignancy [2]. In glioblastoma, Srsf9 promotes cell proliferation and migration. Loss-of-function strategies demonstrated its role in promoting GBM cell growth [3]. In HIV-1 regulation, overexpression of Srsf9 inhibits viral production by inducing imbalanced HIV-1 mRNA splicing [4]. For Caspase-2, knockdown of Srsf9 increases the inclusion of its cassette exon 9, affecting apoptosis-related alternative splicing [5]. In pan-cancer analysis, Srsf9 is upregulated in most cancers and is associated with poor survival and disease progression, making it a potential biomarker for prognosis and immunotherapy [6]. In oral cancer, Srsf9 mediates oncogenic RNA splicing of SLC37A4 via liquid-liquid phase separation, promoting oral cancer progression and cisplatin chemotherapy resistance [7]. In primates, Srsf9 selectively represses ADAR2-mediated editing of brain-specific sites [8]. In ovarian cancer, knockdown of Srsf9 suppresses cell proliferation, invasion, and migration. Srsf9 binds to USP22 mRNA to increase its stability, forming a positive feedback loop with USP22 and ZEB1 to enhance OC malignancy [9]. In colorectal cancer, inhibition of Srsf9 enhances sensitivity to erastin-induced ferroptosis by reducing glutathione peroxidase 4 expression [10].

In conclusion, Srsf9 is a key RNA-binding protein involved in gene expression regulation through alternative splicing and other mechanisms. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in diseases such as cardiac hypertrophy, various cancers, and in processes like HIV-1 regulation and apoptosis. Understanding Srsf9's functions provides potential targets for treating these diseases.

References:

1. Yu, Shuting, Sun, ZhiYong, Ju, Tiantian, Yang, Baofeng, Du, Weijie. 2024. The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2308769. doi:10.1002/advs.202308769. https://pubmed.ncbi.nlm.nih.gov/38810124/

2. Wang, Xiaoyu, Lu, Xiansheng, Wang, Ping, Liang, Li, Lin, Jie. 2022. SRSF9 promotes colorectal cancer progression via stabilizing DSN1 mRNA in an m6A-related manner. In Journal of translational medicine, 20, 198. doi:10.1186/s12967-022-03399-3. https://pubmed.ncbi.nlm.nih.gov/35509101/

3. Luo, Chunyuan, He, Juan, Yang, Yang, Liu, Wenrong, Peng, Yong. 2024. SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression. In Journal of cancer research and clinical oncology, 150, 292. doi:10.1007/s00432-024-05797-0. https://pubmed.ncbi.nlm.nih.gov/38842611/

4. Kim, Ga-Na, Yu, Kyung-Lee, Kim, Hae-In, You, Ji Chang. . Investigation of the effect of SRSF9 overexpression on HIV-1 production. In BMB reports, 55, 639-644. doi:. https://pubmed.ncbi.nlm.nih.gov/36330710/

5. Ha, Jiyeon, Jang, Hana, Choi, Namjeong, Zheng, Xuexiu, Shen, Haihong. 2021. SRSF9 Regulates Cassette Exon Splicing of Caspase-2 by Interacting with Its Downstream Exon. In Cells, 10, . doi:10.3390/cells10030679. https://pubmed.ncbi.nlm.nih.gov/33808656/

6. Liu, Jinhui, Wang, Yuanyuan, Yin, Jian, Yu, Hao, Bai, Jianling. 2022. Pan-Cancer Analysis Revealed SRSF9 as a New Biomarker for Prognosis and Immunotherapy. In Journal of oncology, 2022, 3477148. doi:10.1155/2022/3477148. https://pubmed.ncbi.nlm.nih.gov/35069733/

7. Peng, Qiu, Wang, Lujuan, Long, Ying, Liao, Qianjin, Zhou, Yujuan. 2025. SRSF9 mediates oncogenic RNA splicing of SLC37A4 via liquid-liquid phase separation to promote oral cancer progression. In Journal of advanced research, , . doi:10.1016/j.jare.2025.03.013. https://pubmed.ncbi.nlm.nih.gov/40064440/

8. Shanmugam, Raghuvaran, Zhang, Fan, Srinivasan, Harini, Meaney, Michael J, Tan, Meng How. . SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates. In Nucleic acids research, 46, 7379-7395. doi:10.1093/nar/gky615. https://pubmed.ncbi.nlm.nih.gov/29992293/

9. Wang, Jing, Hu, Ming, Min, Jie, Li, Xin. 2024. A positive feedback loop of SRSF9/USP22/ZEB1 promotes the progression of ovarian cancer. In Cancer biology & therapy, 25, 2427415. doi:10.1080/15384047.2024.2427415. https://pubmed.ncbi.nlm.nih.gov/39530604/

10. Wang, Rui, Su, Qi, Yin, Hongzhuan, Lv, Chi, Yan, Zhaopeng. 2021. Inhibition of SRSF9 enhances the sensitivity of colorectal cancer to erastin-induced ferroptosis by reducing glutathione peroxidase 4 expression. In The international journal of biochemistry & cell biology, 134, 105948. doi:10.1016/j.biocel.2021.105948. https://pubmed.ncbi.nlm.nih.gov/33609745/