An ER-targeted electronic-switched cascade probe for synchronous dual-channel imaging of H2S and HClO during liver fibrosis.

چکیده اصلی

BACKGROUND: The endoplasmic reticulum (ER) relies on a delicate redox balance, primarily orchestrated by crucial biomolecules like hydrogen sulfide (H2S) and hypochlorous acid (HClO). The synchronous monitoring of these multiple biomarkers is critical for deciphering the complex redox signaling intricately associated with pathological processes such as liver fibrosis. While simultaneous dual-channel imaging offers a comprehensive view of cellular redox remodeling, developing precise analytical tools remains highly challenging. Traditional cascade-responsive fluorescent probes inherently suffer from strict activation sequences, severe signal crosstalk, and limited deep-tissue penetration, which unequivocally impede accurate in vivo evaluations. RESULTS: We developed an ER-targeted fluorescent probe (PD) integrating a phenothiazine-coumarin fluorophore with a 2,4-dinitrophenyl (DNP) moiety to independently image H2S and HClO. Reaction with H2S triggers thiolysis, eliciting distinct near-infrared (NIR) emission. Conversely, HClO selectively oxidizes the sulfur core, shifting the scaffold to an acceptor-π-acceptor (A-π-A) architecture with green emission. Uniquely, this oxidized sulfoxide center exerts a potent "remote inductive effect," activating the distal DNP-linked electrophilic site to enable a solvent-mediated 1,6-cascade elimination. This electronic-switched mechanism was rigorously validated by HRMS and density functional theory calculations. Biologically, PD independently mapped endogenous H2S/HClO fluctuations, capturing complex dual-directional redox remodeling during chemically induced ER stress. Capitalizing on its deep-tissue NIR emission, PD achieved exceptional high-contrast intravital tracking of ER-associated redox dynamics in a mouse model of liver fibrosis. SIGNIFICANCE AND NOVELTY: This work establishes a highly novel electronic-switched cascade mechanism driven by a unique remote inductive effect, successfully overcoming traditional signal crosstalk and strict activation sequence limitations. We conclude that PD serves as an exceptionally robust analytical platform for real-time dual-channel monitoring. Significantly, this strategy provides a powerful optical tool for elucidating the complex physiological mechanisms underlying fibro-inflammatory diseases.

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