Tnfsf8, also known as CD153, is a member of the tumor necrosis factor superfamily. It plays a role in immune-related processes. CD153/CD30 signaling, involving Tnfsf8, promotes age-dependent tertiary lymphoid tissue expansion and kidney injury, indicating its importance in kidney-related immune-mediated diseases [2]. Tnfsf8-related pathways may be involved in inflammatory signaling, as suggested by the convergence of candidate causal genes on inflammatory pathways in the study of IgA nephropathy, where Tnfsf8 was among the new risk loci identified [1].

Genetic variants in Tnfsf8 are associated with the risk of various diseases. For example, in a Chinese high-risk population, SNPs in Tnfsf8 are associated with an increased risk of HCV infection [6]. TNFSF8 regulatory variants are associated with excessive inflammatory responses in leprosy type 1 reaction patients, indicating its role in modulating the host's inflammatory response during infection [9]. Moreover, age-dependent associations between Tnfsf8 variants and leprosy type 1 reaction have been observed, suggesting that the genetic control of Tnfsf8-related gene expression may vary across the human lifespan [7]. In non-small cell lung cancer, hypomethylated pDMRs of Tnfsf8 may be potential predictive biomarkers for anti-PD-1 immunotherapy [3]. In skin cancers, Tnfsf8 is identified as a promising druggability candidate for basal cell carcinoma [4]. In postmenopausal osteoporosis, Tnfsf8 is among the immune-related differentially expressed genes potentially serving as a diagnostic biomarker [5]. Additionally, miR-483-5p targets Tnfsf8 to regulate the AMPK/JNK pathway, playing a neuroprotective role after cardiac arrest [8].

In conclusion, Tnfsf8 is crucial in multiple disease-related immune and inflammatory processes. Studies on genetic variants and regulatory mechanisms of Tnfsf8 in various diseases, such as HCV infection, leprosy type 1 reaction, non-small cell lung cancer, skin cancers, postmenopausal osteoporosis, and post-cardiac arrest brain injury, have enhanced our understanding of its functions. These findings provide potential directions for developing targeted therapies for these diseases.

References:

1. Kiryluk, Krzysztof, Sanchez-Rodriguez, Elena, Zhou, Xu-Jie, Zhang, Hong, Gharavi, Ali G. 2023. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. In Nature genetics, 55, 1091-1105. doi:10.1038/s41588-023-01422-x. https://pubmed.ncbi.nlm.nih.gov/37337107/

2. Sato, Yuki, Oguchi, Akiko, Fukushima, Yuji, Minato, Nagahiro, Yanagita, Motoko. . CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. In The Journal of clinical investigation, 132, . doi:10.1172/JCI146071. https://pubmed.ncbi.nlm.nih.gov/34813503/

3. Cho, Jae-Won, Hong, Min Hee, Ha, Sang-Jun, Lee, Insuk, Kim, Hye Ryun. 2020. Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer. In Experimental & molecular medicine, 52, 1550-1563. doi:10.1038/s12276-020-00493-8. https://pubmed.ncbi.nlm.nih.gov/32879421/

4. Li, Yajia, Li, Qiangxiang, Cao, Ziqin, Wu, Jianhuang. 2024. Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers. In Communications biology, 7, 857. doi:10.1038/s42003-024-06538-2. https://pubmed.ncbi.nlm.nih.gov/39003418/

5. Fang, Shenyun, Ni, Haonan, Zhang, Qianghua, Zhang, Weili, Li, Haidong. 2024. Integrated single-cell and bulk RNA sequencing analysis reveal immune-related biomarkers in postmenopausal osteoporosis. In Heliyon, 10, e38022. doi:10.1016/j.heliyon.2024.e38022. https://pubmed.ncbi.nlm.nih.gov/39328516/

6. Fu, Zuqiang, Cai, Weihua, Shao, Jianguo, Huang, Peng, Yue, Ming. 2021. Genetic Variants in TNFSF4 and TNFSF8 Are Associated With the Risk of HCV Infection Among Chinese High-Risk Population. In Frontiers in genetics, 12, 630310. doi:10.3389/fgene.2021.630310. https://pubmed.ncbi.nlm.nih.gov/33841497/

7. Fava, Vinicius M, Sales-Marques, Carolinne, Alcaïs, Alexandre, Moraes, Milton O, Schurr, Erwin. 2017. Age-Dependent Association of TNFSF15/TNFSF8 Variants and Leprosy Type 1 Reaction. In Frontiers in immunology, 8, 155. doi:10.3389/fimmu.2017.00155. https://pubmed.ncbi.nlm.nih.gov/28261213/

8. Zhang, Qiang, Zhan, Haohong, Liu, Cong, Hu, Chunlin, Liao, Xiaoxing. 2022. Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the TNFSF8/AMPK/JNK Signaling Pathway. In Cellular and molecular neurobiology, 43, 2179-2202. doi:10.1007/s10571-022-01296-3. https://pubmed.ncbi.nlm.nih.gov/36266523/

9. Fava, Vinicius M, Cobat, Aurélie, Van Thuc, Nguyen, Alcaïs, Alexandre, Schurr, Erwin. 2014. Association of TNFSF8 regulatory variants with excessive inflammatory responses but not leprosy per se. In The Journal of infectious diseases, 211, 968-77. doi:10.1093/infdis/jiu566. https://pubmed.ncbi.nlm.nih.gov/25320285/