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

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.