Prdx5, short for peroxiredoxin 5, is an enzyme that detoxifies reactive oxygen species. It is involved in multiple pathways such as the DNA damage response (DDR) pathway, thioredoxin/peroxiredoxin pathway, Keap1-Nrf2 signaling axis, TLR4/NF-κB pathway, and SIRT3-mediated antioxidant and anti-inflammatory activities [1,2,4,7,8]. Prdx5 is of great biological importance as it impacts various cellular processes and is associated with numerous diseases [1-10]. Genetic models can be valuable for studying its functions.

Knockdown of Prdx5 led to DNA damage, manifested by the induction of phosphorylated histone H2AX (γ-H2AX) and p53-binding protein 1 (53BP1), indicating its role in regulating DDR through the ATM/p53/Sirt2 signaling cascade [1]. In castration-resistant prostate cancer, PRDX5 promotes AR inhibitor resistance and CRPC development, and its inhibition suppresses DTP cell proliferation [2]. In TSC2 mutant cells, auranofin and rapamycin reduced Prdx5 levels, making ER stress-induced cell death possible [3]. Prdx5 deficiency worsened MSU crystal-induced inflammation, suggesting its protective role [4]. In NSCLC, high expression of Nrf2 and PRDX5 was associated with a worsened prognosis, and their interaction promoted NSCLC development [5]. In castration-resistant prostate cancer, inhibition of PRDX5 enzyme activity disrupted its interaction with NRF2, leading to apoptosis of DTP cells and slowing CRPC progression [6]. Silencing of Prdx5 in macrophages suppressed M1 polarization, reducing apoptosis in prostate epithelial cells and mitigating experimental autoimmune prostatitis [7].

In conclusion, Prdx5 is crucial for maintaining cellular homeostasis by regulating DNA damage response, inflammation, and cell survival. Studies using gene knockdown (akin to loss-of-function in KO/CKO models) have revealed its role in diseases like DNA-damage-related disorders, castration-resistant prostate cancer, tuberous sclerosis complex-associated neoplasia, gout, NSCLC, and chronic prostatitis. Understanding Prdx5 functions through these model-based research provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Agborbesong, Ewud, Zhou, Julie X, Li, Linda X, Calvet, James P, Li, Xiaogang. . Prdx5 regulates DNA damage response through autophagy-dependent Sirt2-p53 axis. In Human molecular genetics, 32, 567-579. doi:10.1093/hmg/ddac218. https://pubmed.ncbi.nlm.nih.gov/36067023/

2. Wang, Rong, Mi, Yuanyuan, Ni, Jiang, Feng, Ninghan, Chen, Yong Q. 2023. Identification of PRDX5 as A Target for The Treatment of Castration-Resistant Prostate Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2304939. doi:10.1002/advs.202304939. https://pubmed.ncbi.nlm.nih.gov/38115765/

3. Bovari-Biri, Judit, Abdelwahab, ElHusseiny Mohamed Mahmoud, Garai, Kitti, Pongracz, Judit E. 2023. Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms. In Cells, 12, . doi:10.3390/cells12131713. https://pubmed.ncbi.nlm.nih.gov/37443747/

4. Jiang, Hui, Song, DianZe, Zhou, Xiaoqin, Dai, Qian, Zeng, Mei. 2023. Maresin1 ameliorates MSU crystal-induced inflammation by upregulating Prdx5 expression. In Molecular medicine (Cambridge, Mass.), 29, 158. doi:10.1186/s10020-023-00756-w. https://pubmed.ncbi.nlm.nih.gov/37996809/

5. Chen, Xinming, Cao, Xiang, Xiao, Weizhang, Li, Ben, Xue, Qun. 2020. PRDX5 as a novel binding partner in Nrf2-mediated NSCLC progression under oxidative stress. In Aging, 12, 122-137. doi:10.18632/aging.102605. https://pubmed.ncbi.nlm.nih.gov/31899687/

6. Wang, Rong, Pan, Yu, Zhang, Lan, Mi, Yuanyuan, Chen, Yong Q. 2024. Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development. In International journal of biological macromolecules, 278, 134844. doi:10.1016/j.ijbiomac.2024.134844. https://pubmed.ncbi.nlm.nih.gov/39168191/

7. Wu, Weikang, Meng, Tong, Wang, Yufan, Chen, Jing, Liang, Chaozhao. 2025. Prdx5 regulates macrophage polarization by modulating the TLR4/NF-κB pathway to promote apoptosis in chronic prostatitis. In International immunopharmacology, 151, 114332. doi:10.1016/j.intimp.2025.114332. https://pubmed.ncbi.nlm.nih.gov/40015209/

8. Liu, Li-Wei, Xie, Yu, Li, Guan-Qun, Li, Le, Sun, Bei. 2022. Gut microbiota-derived nicotinamide mononucleotide alleviates acute pancreatitis by activating pancreatic SIRT3 signalling. In British journal of pharmacology, 180, 647-666. doi:10.1111/bph.15980. https://pubmed.ncbi.nlm.nih.gov/36321732/