From Proteostasis Disruption to Stone Formation: Ubiquitin-Dependent Regulatory Networks in Calcium Oxalate...

Calcium oxalate (CaOx) nephrolithiasis is a multistep disease process in which urinary supersaturation and crystallization interact with renal tissue responses to promote persistent mineral deposition and stone development. Two related pathological settings are particularly relevant: tubular crystal-epithelial interactions, where crystal-induced cellular stress, inflammation, regulated cell death, and epithelial surface remodeling favor crystal adhesion and retention; and Randall's plaque (RP)-associated papillary mineralization, where interstitial mineral deposition and plaque exposure provide a substrate for CaOx overgrowth and stone initiation. Although pathologically distinct, both involve changes in protein homeostasis and cellular phenotype. The ubiquitin-proteasome system (UPS) and deubiquitinating enzymes (DUBs), through reversible control of protein stability, localization, and signaling, may regulate multiple steps in these processes. This review examines ubiquitin-dependent regulation across tubular injury and crystal retention, inflammatory signaling, cellular stress and organelle homeostasis, regulated cell death, and RP-associated remodeling. Disease-specific studies have identified mechanistically resolved pathways, including the VHL-BICD2-STAT1, Lgals3-TRIM21-PKM2, and PRMT1-UBE2M-NEDD4-PPARγ axes in CaOx-associated tubular pathology, as well as the OMD-NEDD4-BMP2 and TRAF1-TRAF2/CBLC axes in RP-associated pathology. Other findings implicate ubiquitin-dependent regulation in mitochondrial quality control, inflammation, epithelial remodeling, and cell death, but the evidence remains uneven. Only a limited number of E3 ligase/DUB-substrate relationships have been established directly in CaOx or RP models, while many candidate mechanisms derive from other renal or non-renal disease contexts. Viewed through the lens of proteostasis, altered protein fate may connect cellular stress with epithelial dysfunction, crystal retention, and papillary mineralization without implying a single route to stone formation. Defining CaOx-specific ubiquitin networks will require quantitative ubiquitinomics and ubiquitin-chain analysis integrated with spatial approaches and causal validation in disease-relevant models and human tissues. Such studies may reveal therapeutically tractable targets with sufficient molecular and renal selectivity.