Molecular Mechanisms of Early Renal Fibrosis: Integrating Multi-Omics Evidence for Translational Nephrology

Early renal fibrosis represents a critical and potentially reversible stage in the progression of chronic kidney disease, yet its complex molecular underpinnings remain incompletely understood. Traditional histopathological and single-pathway approaches have provided limited insight into the dynamic and heterogeneous processes driving fibrotic initiation. Recent advances in high-throughput omics technologies have enabled comprehensive interrogation of molecular alterations across multiple regulatory layers, offering new opportunities to elucidate early fibrogenic mechanisms. This comprehensive review synthesizes evidence from genomic, epigenomic, transcriptomic, proteomic, and metabolomic studies to define the molecular landscape of early renal fibrosis from a systems biology perspective. Integrated multi-omics analyses reveal that early fibrogenesis arises from coordinated dysregulation of profibrotic signaling pathways, metabolic reprogramming, inflammatory activation, and extracellular matrix remodeling rather than isolated molecular events. Single-cell and spatial transcriptomic studies further demonstrate that distinct cell-state transitions and spatially restricted interactions among epithelial, stromal, endothelial, and immune cells shape fibrotic niches prior to overt structural damage. Network-based integration identifies convergent molecular modules and key regulatory hubs that govern fibrosis initiation and progression, providing mechanistic insights with translational relevance. Collectively, these findings underscore the value of multi-omics integration for advancing early detection strategies, therapeutic target prioritization, and precision nephrology. While challenges remain, including limited longitudinal human datasets and technical barriers to data integration, multi-omics approaches are poised to transform understanding and management of early renal fibrosis by enabling mechanism-driven, individualized intervention strategies.