Glomerulosclerosis in 2026: From Pathophysiological Mechanisms to Precision Therapeutics

Glomerulosclerosis is not an independent disease entity but rather a common histopathological endpoint shared by diverse glomerular diseases and chronic kidney disorders. It represents the final common pathway of progressive glomerular injury and is a major determinant of chronic kidney disease (CKD) progression. Accordingly, this review focuses on the shared cellular and molecular mechanisms that drive glomerulosclerosis, together with current diagnostic strategies, mechanism-based therapeutic approaches, and future directions toward precision nephrology. We begin by summarizing the structural and functional features of the glomerulus and outlining the key molecular mechanisms that drive sclerosis, including podocyte loss, mesangial matrix expansion, endothelial dysfunction, inflammation, and fibrosis-related signaling pathways. The clinical and pathological classifications of glomerular diseases associated with glomerulosclerosis—ranging from primary and secondary focal segmental glomerulosclerosis (FSGS) to diabetic, hypertensive, and immune-mediated forms—are discussed in detail. We further review current diagnostic approaches, including renal biopsy patterns, emerging biomarkers, and novel imaging and digital pathology tools that enable earlier and more precise assessment of disease severity. Recent advances in treatment are summarized across conservative, immunologic, and targeted therapeutic categories, with emphasis on SGLT2 inhibitors, endothelin receptor antagonists, immunomodulatory agents, and antifibrotic compounds. Finally, we highlight rapidly evolving therapeutic and technological advances, including podocyte-directed interventions, APOL1-targeted therapies, RNA- and gene-based therapeutics, and artificial intelligence-driven precision nephrology. These emerging approaches are reshaping the management paradigm of glomerular diseases by enabling molecular disease stratification and personalized treatment strategies. Despite substantial progress, significant unmet needs remain, particularly concerning early detection, individualized treatment selection, and the marked heterogeneity of disease mechanisms across patient populations. Overall, this review provides an integrated framework for understanding glomerulosclerosis as a shared pathological endpoint of diverse glomerular diseases and highlights emerging mechanism-based therapeutic strategies that support the transition toward precision nephrology.