Fxyd5, also known as Dysadherin or RIC, is a single-span type I membrane protein. It serves as an auxiliary subunit of the Na(+)/K(+)-ATPase and plays multiple roles in regulating cellular functions such as modulating cellular junctions, influencing chemokine production, and affecting cell adhesion. It is expressed in various epithelial tissues and is involved in pathways like Akt/mTOR, NF-κB, and TGF-β/SMAD, which are crucial in many biological processes and disease conditions [1].

In hepatocellular carcinoma, down-regulation of Fxyd5 in sorafenib-resistant cells reversed their resistance to the drug, suggesting Fxyd5 enhances resistance by activating the Akt/mTOR signaling pathway [2]. In chondrocytes, silencing Fxyd5 increased cell viability, reduced inflammation-related factors and extracellular matrix degradation by inhibiting the NF-κB pathway [3]. In gastric cancer, reducing Fxyd5 expression inhibited cell invasion, metastasis, proliferation, and reversed drug resistance by modulating the epithelial-mesenchymal transition (EMT) process [4]. In epithelial ovarian cancer, low expression of Fxyd5 reversed cisplatin resistance, reduced cell invasion, migration, and EMT formation [5].

In conclusion, Fxyd5 has diverse functions in regulating cellular processes. Its role in promoting cancer cell resistance to chemotherapy drugs and inflammation-related diseases has been revealed through loss-of-function experiments. These findings emphasize the potential of Fxyd5 as a therapeutic target in cancers like hepatocellular, gastric, and epithelial ovarian cancers, as well as in diseases related to chondrocyte inflammation.

References:

1. Lubarski Gotliv, Irina. 2016. FXYD5: Na(+)/K(+)-ATPase Regulator in Health and Disease. In Frontiers in cell and developmental biology, 4, 26. doi:10.3389/fcell.2016.00026. https://pubmed.ncbi.nlm.nih.gov/27066483/

2. Tan, Xiang-Peng, Xiong, Ben-Han, Zhang, Yuan-Xu, Zuo, Qian, Li, Jing. 2022. FXYD5 promotes sorafenib resistance through the Akt/mTOR signaling pathway in hepatocellular carcinoma. In European journal of pharmacology, 931, 175186. doi:10.1016/j.ejphar.2022.175186. https://pubmed.ncbi.nlm.nih.gov/35977595/

3. Song, Lulu, Li, Xingxing, Sun, Qingwan, Zhao, Yifeng. 2022. Fxyd5 activates the NF‑κB pathway and is involved in chondrocytes inflammation and extracellular matrix degradation. In Molecular medicine reports, 25, . doi:10.3892/mmr.2022.12650. https://pubmed.ncbi.nlm.nih.gov/35191523/

4. Mao, Yuning, Hu, Yaohua, Meng, Han, Ge, Xu, Shi, Changhong. 2025. FXYD5 regulates gastric cancer cell metastasis and drug resistance by EMT modulation. In Cancer gene therapy, 32, 318-326. doi:10.1038/s41417-025-00878-9. https://pubmed.ncbi.nlm.nih.gov/39984673/

5. Liu, Ya-Kun, Jia, Ya-Jing, Liu, Shi-Hao, Shi, Hong-Jie, Ma, Jing. 2021. Low expression of FXYD5 reverses the cisplatin resistance of epithelial ovarian cancer cells. In Histology and histopathology, 36, 535-545. doi:10.14670/HH-18-310. https://pubmed.ncbi.nlm.nih.gov/33570156/