A recent review published in Genes & Diseases by researchers from the University of South China provides a comprehensive overview of the structure and physiological roles of FXYD proteins, their roles in the pathogenesis of various diseases, and highlights these molecules as potential therapeutic targets.

The conserved 35-amino-acid domain, also known as the FXYD motif, is essential for their functions and their interaction with NKA, which influences the pump’s affinity for ATP and its ion transport kinetics in response to varying cellular conditions. Distinct residues flank the conserved FXYD motif, which contribute to their specific regulatory effects and tissue-specific expression patterns, allowing ion transport tailored to the needs of specific organs. For example, (i) FXYD1 in the heart aids in muscle contractility and electrical stability, (ii) FXYD1 interacts with the NKA α1 subunit, contributing to brain development, and (iii) FXYD2 and FXYD4 regulate NKA in renal epithelial cells to maintain blood pressure.

Alterations in the expression of these proteins may contribute to the pathogenesis of various diseases. FXYD5 and FXYD6 play tumor-promoter roles in tongue cancer, ovarian carcinoma, endometrial cancer, breast cancer, thyroid cancer, HCC, and osteosarcoma. FXYD2 acts as a tumor suppressor in ovarian cancer, whereas FXYD3 exhibits a dual role, acting as both a tumor promoter in HCC and breast cancer, and as a suppressor in colorectal and lung cancer.

Similarly, altered expression or dysfunction of FXYD proteins is associated with various diseases across multiple systems, including: (i) various neurological diseases in the brain, such as Rett syndrome, neuropathic pain, Parkinson’s disease, and psychiatric disorders; (ii) heart failure and ventricular arrhythmias in the heart; (iii) atherosclerosis, hypertension, and vascular remodeling in the vascular system; (iv) ARF, ATN, and glomerulonephritis in the renal system; (v) diarrhea, IBD, bacterial infection and HSCR, diabetes, glucose metabolism, and pancreatitis in the digestive system; (vi) inflammatory lung injury in the lungs; and (vii) psoriasis in the skin.
Targeting FXYD1 may improve cardiac function in cardiovascular diseases, while modulating FXYD2 and FXYD4 could aid electrolyte management in renal diseases.

Similarly, targeting FXYD6 and FXYD7 may help improve neurological disorders, and targeting FXYD3 and FXYD5 may improve clinical outcomes in various cancers.
Future research must focus on understanding the role of FXYD in diseases, developing gene therapies, small-molecule inhibitors, and peptide-based treatments, and addressing clinical challenges to validate the safety and efficacy of FXYD-targeted therapies.

In summary, this review describes the physiological and pathological roles of FXYD proteins and emphasizes their potential as therapeutic targets, highlighting future research directions that may lead to new treatments and improved patient outcomes.

Reference

Title of the original paper: The functions of FXYD family members in human health and disease

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101847

Funding Information:

• National Natural Science Foundation of China (No. 81974469, 82472835)
• National Science Foundation of China for Youths (No. 82203166)
• General Project of Hunan Provincial Health Commission Research Program (China) (No. B202302057895)
• Science and Technology Innovation Program of Hunan Province, China (No. 2022RC4044)
• Hunan Province Graduate Research and Innovation Project (China) (No. CX20230951, CX20230952),
• Foundation of Hunan Provincial Key Laboratory (China) (No. 2023TP1014).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.


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