Fxyd5, also known as Dysadherin and RIC, is a single-span type I membrane protein. It acts as an auxiliary subunit of the Na(+)/K(+)-ATPase, playing multiple roles in regulating cellular functions such as modulating cellular junctions, influencing chemokine production, and affecting cell adhesion [1]. It is expressed in various epithelial tissues and is involved in multiple pathways like Akt/mTOR, NF-κB, and TGF-β/SMAD, which are crucial for cell survival, inflammation, and tumor progression [2,3,5].

In hepatocellular carcinoma, knockdown of Fxyd5 in Huh7/sora cells reversed their resistance to sorafenib, indicating that Fxyd5 enhances sorafenib 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 alveolar epithelial cells, Fxyd5 silencing prevented the activation of NF-κB and cytokine secretion in response to LPS, interferon α, and TNF-α, showing its role in lung inflammation and injury [4]. In gastric cancer, reducing Fxyd5 expression inhibited cell invasion, metastasis, and proliferation, and reversed drug resistance by modulating the epithelial-mesenchymal transition process [6].

In conclusion, Fxyd5 is essential in regulating various cellular functions through multiple pathways. Its study using gene-knockdown models has revealed its significance in diseases such as cancer, osteoarthritis, and lung injury. These findings suggest that Fxyd5 could be a potential therapeutic target for treating these diseases.