ROS-Responsive H₂S Release Attenuates Renal Aging by Preserving Mitochondrial Function and Mitigating Oxidative Stress

Cellular senescence is a durable state of cell-cycle arrest, and the progressive accumulation of senescent cells compromises tissue repair and promotes age-related functional decline. ROS drive oxidative stress when excessively produced or inadequately cleared, thereby inducing mitochondrial dysfunction that accelerates senescence. In this work, ROS-responsive branched reductive compound HS-N has been designed and synthesized, which serves as a dual-functional donor: effectively scavenges ROS and simultaneously releases H₂S, thereby converting a toxic stimulus into a beneficial signal. Consistent with the effects against oxidative injury, HS-N attenuated stress-induced senescence and restored fibroblast cells' migratory capacity in scratch wound-healing assays by preserving mitochondrial membrane potential and integrity. In naturally aged mice, repeated intraperitoneal administration of HS-N was well tolerated and significantly lowered serum urea, accompanied by reduced renal NOX4 expression and a decrease in serum IL-1β. Histopathological analysis further indicated attenuation of age-associated glomerular hypertrophy without overt lesions in major organs. These results suggest that HS-N alleviates senescence by stabilizing mitochondrial function and modulating redox-linked inflammatory signaling. This work provides a promising framework and insight into how supramolecular and ROS-responsive regulation leverage a "turn poison into medicine" strategy through ROS-triggered H₂S release.