Stigmasterol-Mediated Targeting of Rho-Associated Coiled-Coil Protein Kinase 1 Ameliorates Diabetic Kidney Disease and Attenuates Renal Tubular Lipid Deposition.

Diabetic kidney disease (DKD) is identified as the major contributor to the development of end-stage renal disease, with its clinical incidence increasing. Emerging studies link DKD closely to renal lipid deposition, tubular injury, and glomerulosclerosis-pathological processes driven by renal lipid metabolism disorders that ultimately induce renal fibrosis. However, targeted therapeutics for renal lipid deposition are scarce. This study fills this research gap: first, clinical database analyses identified a positive correlation between up-regulated rho-associated coiled-coil protein kinase 1 (ROCK1) expression in renal tubules and progressive renal function deterioration in DKD patients, a finding recapitulated in DKD mouse models, which also exhibited renal tubular ROCK1 up-regulation and concomitant lipid accumulation; second, molecular docking, surface plasmon resonance, and cellular thermal shift assay confirm that the natural molecule stigmasterol (ST) binds to ROCK1 and inhibits its expression with a dose-dependent trend; and, third, in vivo and in vitro experiments demonstrate that ST alleviates lipid accumulation, mitochondrial damage, and renal fibrosis in DKD via the ROCK1/p38 mitogen-activated protein kinase/peroxisome proliferator-activated receptor α axis. In conclusion, ST exerts direct renoprotective effects by regulating the ROCK1 pathway to improve renal lipid metabolism, reduce mitochondrial damage, and inhibit fibrosis, highlighting its potential as a novel ROCK1 inhibitor. This study identifies ST as a candidate for targeted intervention in DKD-related lipid metabolism, validates ROCK1 as a therapeutic target, provides an experimental basis for the DKD treatment strategy of "targeting ROCK1 to synergistically improve lipid metabolism and mitochondrial function", and opens new avenues for natural products in metabolism-related nephropathies.