Targeting RNA homeostasis in kidney disease: RNA quality control, therapeutic mechanisms, and pharmacological opportunities

Kidney disease progression is increasingly understood as a failure of cellular stress adaptation, in which renal cells cannot fully restore homeostasis after metabolic, hemodynamic, toxic, or inflammatory injury. Although mitochondrial dysfunction, proteostasis collapse, metabolic rewiring, regulated cell death, and immune activation have been widely studied as therapeutic targets, RNA homeostasis is emerging as a measurable layer of renal stress biology with selected pharmacological entry points. RNA homeostasis encompasses the coordinated regulation of RNA biogenesis, processing, chemical modification, localization, translation, decay, and quality control. These processes influence whether injured kidney cells regain adaptive function or progress toward maladaptive repair, senescence, inflammation, and fibrosis. Recent studies have identified transfer RNA (tRNA)-derived small RNAs, RNA autophagy, N6-methyladenosine RNA methylation, RNA-binding proteins, stress granules, and extracellular RNA signaling as functional regulators of kidney injury and repair. These pathways are increasingly accessible to mechanistic interrogation and, in selected preclinical settings, to modulation by small-molecule enzyme inhibitors, RNA mimics, antisense oligonucleotides, siRNAs, mRNA-based approaches, RNA editing, and kidney-targeted delivery systems. In this review, we synthesize RNA homeostasis as an emerging framework for understanding and potentially targeting kidney disease, while distinguishing mechanisms with causal preclinical support from more speculative therapeutic opportunities. We focus on targetable RNA-homeostatic mechanisms in acute kidney injury, diabetic kidney disease, podocyte injury, and renal fibrosis, and highlight strategies for translating RNA quality-control pathways into biomarkers, pharmacodynamic readouts and candidate disease-modifying interventions.