HSP90-specific inhibitor, PSY-2–12, ameliorates cellular senescence via activating autophagy: A potential senotherapeutic target against acute kidney injury

An unexpected senotherapeutic function of heat shock protein 90 (HSP90) inhibitors—drugs long developed as cancer therapeutics—has recently been revealed. In this study, we employed an HSP90-specific inhibitor, PSY-2–12 (PSY), to explore its potential therapeutic application as a senomorphic agent. We demonstrated that PSY, at non-toxic concentrations, reduces cellular senescence in both cisplatin (CP)-induced senescent kidney proximal tubular cells and angiotensin II-induced senescent human umbilical vein endothelial cells. The anti-senescent effect of PSY was further confirmed in a mouse model of CP-induced acute kidney injury (AKI). PSY treatment attenuated CP-induced kidney injury, as evidenced by decreased levels of urea, creatinine, and kidney injury molecule-1, and ameliorated CP-induced senescence, as shown by reduced β-galactosidase staining and p16 expression, along with increased lamin B1 levels compared with controls. Mechanistically, we found that PSY exerts its senotherapeutic effects through beclin-1–mediated stimulation of autophagy. PSY enhanced beclin-1 expression and autophagic flux in CP-treated proximal tubular cells, while inhibition of autophagy reversed the senotherapeutic effects of PSY. Similarly, beclin-1 knockdown abolished the protective effects. In summary, our results suggest that PSY, an HSP90-specific inhibitor, may serve as a promising senomorphic therapeutic agent for the treatment of AKI.