Silybin Improves Acute Kidney Injury by Regulating HDAC6/NF-κB/NLRP3 Signaling to Reduce Inflammation and Ferroptosis

Inflammation and ferroptosis play a crucial role in cisplatin (CP)-induced acute kidney injury (AKI). Silybin (SYB), a polyphenolic flavonoid, has shown renal protective effects, but its underlying mechanisms remain unclear. CP-induced HK-2 cell and mouse AKI models were used to explore the role of SYB. CCK-8, lactate dehydrogenase release, flow cytometry, and calcein/PI staining, were performed to evaluate cell viability, proliferation, and apoptosis. Oxidative stress and ferroptosis markers were measured, while renal function was assessed by serum creatinine and urea nitrogen. Mitochondrial ultrastructure was examined, and histological staining was conducted to analyze renal pathology and iron deposition. Western blotting detected HDAC6, NF-κB, NLRP3, and ferroptosis-related proteins expression. SYB treatment alleviated CP-induced mitochondrial damage, reduced lactate dehydrogenase release, inflammatory cytokines, oxidative stress, and ferroptosis, and improved proliferation and viability in HK-2 cells. In mice, 100 mg/kg SYB decreased serum creatinine, urea nitrogen, and cytokine levels, while ameliorating renal tissue injury. Mechanistically, SYB downregulated HDAC6 and inhibited NF-κB/NLRP3 activation, thereby suppressing ferroptosis. Notably, overexpression of HDAC6 restored NF-κB/NLRP3 activity and attenuated the protective effects of SYB. In conclusion, SYB mitigates CP-induced AKI by reducing inflammation and ferroptosis by modulating the HDAC6/NF-κB/NLRP3 pathway.