Unraveling the Mystery of Parathyroid Oxyphil Cells in Uremic SHPT: Ongoing Challenges and Multi-Omics Advances

Abstract The parathyroid gland, a pivotal organ regulating calcium and phosphorus homeostasis, harbors two primary cell types: chief cells and the enigmatic oxyphil cells. While scarce in healthy individuals, oxyphil cells undergo pronounced proliferation in uremic secondary hyperparathyroidism (SHPT), and their abundance is strongly associated with resistance to first-line therapies like calcitriol and calcimimetics. This correlation underscores a critical clinical challenge, yet the origin, functional role, and mechanisms driving oxyphil cell proliferation have remained poorly understood. Integrated multi-omics studies have decisively illuminated the underlying mechanisms, revealing uremic milieu-driven transdifferentiation from chief cells to oxyphil cells and the pivotal role of mitochondrial biogenesis activation in this process. This paradigm shift redefines oxyphil cells from passive entities to metabolically hyperactive, autonomous units capable of heightened parathyroid hormone synthesis and secretion. The core mechanism of therapy resistance is explained by the profound downregulation of key regulatory receptors, rendering them insensitive to conventional drugs. This review synthesizes current knowledge and, more importantly, highlights how integrated multi-omics approaches are illuminating the pathobiology of oxyphil cells, providing groundbreaking insights into their function, origin, and proliferation mechanisms. We conclude that these advances are pivotal for developing novel therapeutic strategies to overcome treatment resistance in uremic SHPT.