Gsta4, glutathione transferase α4, is a member of the Phase II detoxifying enzyme superfamily. It plays a crucial role in removing 4-hydroxynonenal (4-HNE), an end product of lipid peroxidation, and is involved in various biological processes related to oxidative stress responses [2,4,5,6,7]. Genetic models, like gene knockout mouse models, have been instrumental in studying its functions.

In gene knockout mouse models, loss of Gsta4 leads to more profound hearing loss in female mice compared to male mice under cisplatin treatment, suggesting its role in reducing cisplatin ototoxicity [2]. In the context of melanoma, up-regulation of Gsta4 enables cancer cells to escape host immunity and gain metastatic ability by acquiring resistance to oxidative stress responses [1]. In oligodendrocyte differentiation, Gsta4 loss impairs differentiation into myelinating oligodendrocytes, and overexpression reduces apoptosis-related factors, indicating its importance in remyelination [3]. Also, Gsta4-deficient mice are more sensitive to skin tumor promotion by TPA, and GSTA4 polymorphisms are associated with human non-melanoma skin cancer risk [8].

In conclusion, Gsta4 is essential for maintaining normal physiological functions by regulating oxidative stress responses. Gene knockout mouse models have revealed its significant roles in diseases such as cisplatin-induced ototoxicity, melanoma metastasis, multiple sclerosis-related remyelination, and non-melanoma skin cancer development. Understanding Gsta4's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Ucche, Sisca, Yokoyama, Satoru, Mojic, Marija, Tahara, Hideaki, Hayakawa, Yoshihiro. . GSTA4 Governs Melanoma Immune Resistance and Metastasis. In Molecular cancer research : MCR, 21, 76-85. doi:10.1158/1541-7786.MCR-22-0369. https://pubmed.ncbi.nlm.nih.gov/36162957/

2. Park, Hyo-Jin, Kim, Mi-Jung, Rothenberger, Christina, Salvi, Richard, Someya, Shinichi. 2019. GSTA4 mediates reduction of cisplatin ototoxicity in female mice. In Nature communications, 10, 4150. doi:10.1038/s41467-019-12073-0. https://pubmed.ncbi.nlm.nih.gov/31515474/

3. Carlström, Karl E, Zhu, Keying, Ewing, Ewoud, Castelo-Branco, Gonçalo, Piehl, Fredrik. 2020. Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis. In Nature communications, 11, 4071. doi:10.1038/s41467-020-17871-5. https://pubmed.ncbi.nlm.nih.gov/32792491/

4. Hayes, John D, Flanagan, Jack U, Jowsey, Ian R. . Glutathione transferases. In Annual review of pharmacology and toxicology, 45, 51-88. doi:. https://pubmed.ncbi.nlm.nih.gov/15822171/

5. Park, Hyo-Jin, Kim, Mi-Jung, Han, Chul, Salvi, Richard, Someya, Shinichi. 2020. Effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss in mice. In Experimental gerontology, 133, 110872. doi:10.1016/j.exger.2020.110872. https://pubmed.ncbi.nlm.nih.gov/32044382/

6. McElhanon, Kevin E, Bose, Chhanda, Sharma, Rajendra, Awasthi, Yogesh C, Singh, Sharda P. . Gsta4 Null Mouse Embryonic Fibroblasts Exhibit Enhanced Sensitivity to Oxidants: Role of 4-Hydroxynonenal in Oxidant Toxicity. In Open journal of apoptosis, 2, . doi:10.4236/ojapo.2013.21001. https://pubmed.ncbi.nlm.nih.gov/24353929/

7. Beneš, Helen, Vuong, Mai K, Boerma, Marjan, Siegel, Eric R, Singh, Sharda P. . Protection from oxidative and electrophilic stress in the Gsta4-null mouse heart. In Cardiovascular toxicology, 13, 347-56. doi:10.1007/s12012-013-9215-1. https://pubmed.ncbi.nlm.nih.gov/23690225/

8. Abel, Erika L, Angel, Joe M, Riggs, Penny K, Wei, Qingyi, DiGiovanni, John. 2010. Evidence that Gsta4 modifies susceptibility to skin tumor development in mice and humans. In Journal of the National Cancer Institute, 102, 1663-75. doi:10.1093/jnci/djq392. https://pubmed.ncbi.nlm.nih.gov/20966433/