Targeting GHSR-1α with silibinin to enhance mitophagy and prevent tubular injury in diabetic kidney disease.

Diabetic kidney disease (DKD) remains a leading cause of global renal failure, with tubular injury driven by mitochondrial dysfunction representing a critical yet therapeutically unaddressed mechanism. Although the flavonolignan silibinin has demonstrated renoprotective potential, its precise molecular targets and mechanisms in DKD have remained unclear. In this study, we combined integrated computational docking, biophysical assays, and comprehensive in vivo and in vitro models to investigate silibinin's interaction with the growth hormone secretagogue receptor-1α (GHSR-1α). We demonstrated that silibinin directly binds to and activates GHSR-1α, triggering a signaling cascade characterized by liver kinase B1 (LKB1) phosphorylation, nuclear export, and complex formation with mouse protein 25 (MO25). This interaction leads to sustained AMP-activated protein kinase (AMPK) activation, which in turn restores mitophagy and alleviates oxidative stress, inflammation, and apoptosis in renal tubular cells. Crucially, these protective effects were abolished by the genetic or pharmacological inhibition of GHSR-1α. Collectively, these findings establish that silibinin mitigates DKD-associated tubular injury by activating the GHSR-1α/LKB1/AMPK axis to promote mitochondrial quality control.