Snx3, a sorting nexin gene, is a retromer-associated cargo binding protein with crucial functions in various cellular processes. It is involved in pathways such as Wnt/β -catenin signaling, endosomal sorting, and ferroptosis regulation, and is important for maintaining normal physiological functions in organisms [3,4,5,6,7,8]. Genetic models, especially knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions.

In cardiomyocytes, Snx3-cKO mice have shown that Snx3 exacerbates doxorubicin-induced cardiomyopathy. Deletion of Snx3 in these mice normalized heart contractile/relaxation function, reduced cardiac injury biomarkers, mitigated the inflammatory response and oxidative stress, and alleviated doxorubicin-induced cell death, ER stress, and mitochondrial dysfunction. Mechanistically, Snx3 promotes ferroptosis through the regulation of GPX4-mediated and TFRC-dependent ferroptosis [2,3]. In colorectal cancer, honokiol enhances the sensitivity of cetuximab in KRASG13D mutant CRC by destroying the SNX3-retromer complex, suppressing SNX3-retromer mediated trafficking, and inhibiting autophagy and macropinocytosis fluxes [1].

In summary, Snx3 is essential for multiple biological processes, including maintaining normal heart function and influencing cancer cell responses. The study of Snx3 KO/CKO mouse models has significantly contributed to understanding its role in doxorubicin-induced cardiomyopathy and in enhancing the sensitivity of anti-cancer drugs in specific colorectal cancer mutants, providing potential therapeutic strategies for these diseases.

References:

1. Zhu, Qianru, Zhang, Ruonan, Gu, Xiaoqing, Xie, Tian, Sui, Xinbing. 2024. Honokiol enhances the sensitivity of cetuximab in KRASG13D mutant colorectal cancer through destroying SNX3-retromer complex. In Theranostics, 14, 5443-5460. doi:10.7150/thno.97180. https://pubmed.ncbi.nlm.nih.gov/39310106/

2. Huang, Shuai, Zou, Fan, Zhou, Hao, He, Jinyuan. 2024. SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis. In International journal of medical sciences, 21, 1629-1639. doi:10.7150/ijms.95466. https://pubmed.ncbi.nlm.nih.gov/39006843/

3. Yu, Wenjing, Hu, Yuehuai, Liu, Zhiping, Liu, Peiqing, Lu, Jing. 2023. Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis. In Acta pharmaceutica Sinica. B, 13, 4875-4892. doi:10.1016/j.apsb.2023.08.016. https://pubmed.ncbi.nlm.nih.gov/38045054/

4. Cicek, Esra, Circir, Ayca, Oyken, Merve, Sahin, Ozgur, Erson-Bensan, Ayse Elif. 2021. EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers. In Oncogene, 41, 220-232. doi:10.1038/s41388-021-02086-9. https://pubmed.ncbi.nlm.nih.gov/34718348/

5. Brown, Heather Mary, Murray, Stephen A, Northrup, Hope, Au, Kit Sing, Niswander, Lee A. 2020. Snx3 is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling. In Development (Cambridge, England), 147, . doi:10.1242/dev.192518. https://pubmed.ncbi.nlm.nih.gov/33214242/

6. Pan, Biran, Zhang, Tongtong, Yang, Wei, Zhao, Cong, Guo, Yuanbiao. 2019. SNX3 suppresses the migration and invasion of colorectal cancer cells by reversing epithelial-to-mesenchymal transition via the β-catenin pathway. In Oncology letters, 18, 5332-5340. doi:10.3892/ol.2019.10860. https://pubmed.ncbi.nlm.nih.gov/31612043/

7. McGough, Ian J, de Groot, Reinoud E A, Jellett, Adam P, Korswagen, Hendrik C, Cullen, Peter J. 2018. SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. In Nature communications, 9, 3737. doi:10.1038/s41467-018-06114-3. https://pubmed.ncbi.nlm.nih.gov/30213940/

8. Chen, Caiyong, Garcia-Santos, Daniel, Ishikawa, Yuichi, Ponka, Prem, Paw, Barry H. 2013. Snx3 regulates recycling of the transferrin receptor and iron assimilation. In Cell metabolism, 17, 343-52. doi:10.1016/j.cmet.2013.01.013. https://pubmed.ncbi.nlm.nih.gov/23416069/