PARP9, a member of the PARP family, is involved in multiple biological processes. It has been associated with pathways such as interferon-induced ADP-ribosylation, lipid metabolism, and plays a role in the regulation of immune responses, apoptosis, and fibrosis [1,2,3,4,5]. Genetic models like gene knockout (KO) mouse models can be valuable for studying its functions in vivo.

In mice, PARP9 deficiency leads to enhanced susceptibility to RNA virus infections due to impaired type I interferon production, suggesting its critical role as a non-canonical RNA sensor for RNA viruses in dendritic cells [5]. In a rat model of distal middle cerebral artery occlusion (dMCAO), PARP9 knockdown reduced neuronal apoptosis, neuroinflammation, and microglial activation in the ipsilateral thalamus and hippocampus, while overexpression exacerbated these outcomes. The mechanism involves the PI3K pathway, indicating that PARP9 promotes neural damage and cognitive decline after cerebral infarction [4]. In breast cancer cell lines, PARP9-knockdown inhibited cell migration, suggesting its role in promoting breast cancer progression [6].

In summary, PARP9 has essential functions in immune responses, especially in antiviral defense, and in disease conditions such as cerebral infarction-related neural damage and breast cancer progression. Studies using KO or knockdown models have revealed its contribution to these specific disease areas, highlighting its potential as a therapeutic target.

References:

1. Kar, Pulak, Chatrin, Chatrin, Đukić, Nina, Smith, Rebecca, Ahel, Ivan. 2024. PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation. In The EMBO journal, 43, 2929-2953. doi:10.1038/s44318-024-00126-0. https://pubmed.ncbi.nlm.nih.gov/38834853/

2. Szántó, Magdolna, Gupte, Rebecca, Kraus, W Lee, Pacher, Pal, Bai, Peter. 2021. PARPs in lipid metabolism and related diseases. In Progress in lipid research, 84, 101117. doi:10.1016/j.plipres.2021.101117. https://pubmed.ncbi.nlm.nih.gov/34450194/

3. Chen, Nannan, Zhang, Lianzhi, Zhong, Zhang, Wang, Jiahong, Zheng, Pengxiang. 2024. PARP9 affects myocardial function through TGF-β/Smad axis and pirfenidone. In Biomolecules & biomedicine, 24, 1199-1215. doi:10.17305/bb.2024.10246. https://pubmed.ncbi.nlm.nih.gov/39213416/

4. Liao, Mengshi, Long, Xiya, Chen, Yicong, Xu, Xiangming, Fan, Yuhua. 2025. PARP9 exacerbates apoptosis and neuroinflammation via the PI3K pathway in the thalamus and hippocampus and cognitive decline after cortical infarction. In Journal of neuroinflammation, 22, 43. doi:10.1186/s12974-025-03374-x. https://pubmed.ncbi.nlm.nih.gov/39980030/

5. Xing, Junji, Zhang, Ao, Du, Yong, Li, Xian Chang, Zhang, Zhiqiang. 2021. Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells. In Nature communications, 12, 2681. doi:10.1038/s41467-021-23003-4. https://pubmed.ncbi.nlm.nih.gov/33976210/

6. Tang, Xinghong, Zhang, Hongying, Long, Yan, Jiang, Yangfu, Jing, Jing. 2018. PARP9 is overexpressed in human breast cancer and promotes cancer cell migration. In Oncology letters, 16, 4073-4077. doi:10.3892/ol.2018.9124. https://pubmed.ncbi.nlm.nih.gov/30128030/