Hydrogen Sulfide Attenuates Cisplatin-Induced Acute Kidney Injury via Dual Inhibition of Apoptosis and Pyroptosis

<b>Purpose:</b> Cisplatin chemotherapy is complicated by acute kidney injury (cis-AKI), driven by regulated cell death pathways, including apoptosis and pyroptosis. However, the temporal relationship between apoptosis and pyroptosis in cis-AKI remains unclear. This study investigated the roles of these pathways and evaluated the renoprotective effect of the hydrogen sulfide (H₂S) donor GYY4137. <b>Method:</b> Cis-AKI was modeled in mice and HK2 cells, divided into control, cisplatin, and cisplatin + GYY groups. Kidney function parameters, histopathology, and cell death were evaluated. Markers of apoptosis and pyroptosis, along with the H₂S-producing enzyme, were analyzed. <b>Results:</b> Renal impairment progressed from BUN elevation to increased Scr, coupled with aggravated renal tissue damage. Apoptotic signaling peaked at 24 h, evidenced by a raised Bax/Bcl-2 ratio and caspase-3 cleavage. Pyroptosis pathways, via both NLRP3/caspase-1/GSDMD and caspase-3/GSDME axes, were activated later at 72 h, with concurrent rises in IL-1β and IL-18. GYY4137 treatment significantly ameliorated renal dysfunction, reducing serum creatinine and BUN levels by 22.64% and 22.5%, respectively. It suppressed both the early apoptotic and delayed pyroptosis cascades without reversing CBS downregulation. <b>Conclusions:</b> GYY4137 mitigated both apoptosis and pyroptosis, offering a promising multi-targeted therapy for cis-AKI.