Wang_2026_J.Med.Chem_69_8036

Drug-induced liver injury (DILI) in diabetes remains a critical and clinically challenging disease due to the lack of effective theranostic tools. Herein, we report SKCLS, a carboxylesterase (CE, an enzyme overexpressed in the liver)-activatable hydrogen sulfide (H(2)S) donor integrating near-infrared fluorescence and chemiluminescence (NIRF/CHL) imaging for DILI theranostics in diabetes. Upon CE-mediated hydrolysis, SKCLS undergoes a self-immolative reaction to generate NIRF and CHL signals for the precise tracking of liver repair processes and the release of carbonyl sulfide (COS), which can be rapidly converted to H(2)S via carbonic anhydrase (CA). The in situ delivery of H(2)S effectively alleviates oxidative injury by activating the Keap1-Nrf2/ARE pathway and accelerates hepatic functional recovery. This study successfully establishes an innovative theranostic platform that combines dual-mode diagnosis and H(2)S therapy. It not only effectively solves the theranostic problems associated with DILI management in diabetes but also opens up new avenues for managing other injury-related liver diseases.