# The Role of Protein Post-Translational Modifications in the Pathogenesis of Nephrolithiasis: Mechanistic Insights and Translational Potential

## TL;DR

Protein modifications play a key role in kidney stone formation and could lead to new treatments.

## Contribution

This paper reveals how post-translational modifications regulate kidney stone disease mechanisms and suggests targeting these modifications as a novel therapy.

## Key findings

- Protein post-translational modifications regulate crystal-cell adhesion and cell death pathways in kidney stones.
- The kidney stone environment shapes these modifications, influencing injury and repair processes.
- Targeting PTM-regulating enzymes offers a new strategy to prevent and manage kidney stones.

## Abstract

What are the main findings?
Protein post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination act as central “molecular switches” that orchestrate crystal-cell adhesion, oxidative stress, inflammatory signaling, and diverse programmed cell death pathways (ferroptosis, pyroptosis, necroptosis) in nephrolithiasis.The kidney stone microenvironment (hyperoxaluria, oxidative stress, metabolic reprogramming) actively shapes the PTM landscape of key proteins, creating a complex regulatory network that determines the balance between renal injury and repair.

Protein post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination act as central “molecular switches” that orchestrate crystal-cell adhesion, oxidative stress, inflammatory signaling, and diverse programmed cell death pathways (ferroptosis, pyroptosis, necroptosis) in nephrolithiasis.

The kidney stone microenvironment (hyperoxaluria, oxidative stress, metabolic reprogramming) actively shapes the PTM landscape of key proteins, creating a complex regulatory network that determines the balance between renal injury and repair.

What is the implication of the main finding?
Targeting specific PTM-regulating enzymes (e.g., Sirt1 activators, HDAC2 inhibitors, AMPK activators) represents a promising novel therapeutic strategy to interrupt stone formation and halt disease progression.Deciphering the “PTM code” that integrates microenvironmental signals to dictate cell fate decisions provides a new framework for understanding stone pathogenesis and developing precision intervention strategies.

Targeting specific PTM-regulating enzymes (e.g., Sirt1 activators, HDAC2 inhibitors, AMPK activators) represents a promising novel therapeutic strategy to interrupt stone formation and halt disease progression.

Deciphering the “PTM code” that integrates microenvironmental signals to dictate cell fate decisions provides a new framework for understanding stone pathogenesis and developing precision intervention strategies.

Nephrolithiasis is a prevalent urological disorder worldwide, whose pathogenesis involves a complex network of crystal formation, cellular injury, and microenvironmental dysregulation. As a critical mechanism for regulating cellular functions, protein post-translational modifications (PTMs) have been increasingly implicated in multiple facets of kidney stone formation, including crystal–cell interactions, oxidative stress responses, and inflammatory signaling pathways. This review systematically synthesizes the biochemical foundations of PTMs, the molecular microenvironment of nephrolithiasis, and the roles of key modifications such as phosphorylation and acetylation in the pathogenesis of calculi. It further explores the translational potential of PTM detection technologies in clinical practice. Current evidence indicates that PTMs influence the nucleation, growth, and aggregation of crystals by modulating the activity of pro-/anti-lithogenic proteins, the expression of cell adhesion molecules, and inflammatory pathways. Consequently, therapeutic strategies targeting PTMs may offer novel avenues for the prevention and management of kidney stones. Future research should focus on integrating multi-omics approaches with functional validation to elucidate the dynamic regulatory networks of PTMs within the stone microenvironment, thereby advancing the development of precision medicine.