Electronic cloud-regulation strategy enabling rapid and sensitive near-infrared detection of ONOO⁻ for dynamic monitoring of ferroptosis-mediated drug-induced liver injury
Yongchuang Li , Haiyue Liu , Yuru Liu , Shaowei Wang , Caixia Yin , Fangjun Huo
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引用次数: 0
Abstract
Drug-induced liver injury (DILI) is caused by hepatotoxic effects resulting from drug metabolism. Extensive studies have demonstrated a close association between DILI progression and ferroptosis, a process characterized by redox imbalance triggered by lipid peroxidation. As a key product of redox imbalance and a critical biomarker of DILI, peroxynitrite (ONOO-) plays a pivotal regulatory role in ferroptosis. To elucidate the precise mechanism of ONOO- in ferroptosis-mediated DILI, there is an urgent need for ONOO- fluorescent probes with high specificity, sensitivity and signal-to-noise ratio. This study innovatively modified the traditional pyridine hemicyanine fluorophore into a quinoline hemicyanine structure, achieving a red-shifted fluorescence emission wavelength through extended conjugation and enhanced electron delocalization. Systematic site screening identified diphenyl phosphate ester as the optimal reaction site, demonstrating exceptional specificity, sensitivity and 75 s response characteristics. By conjugating the optimized fluorophore with the reaction site via nucleophilic substitution, we successfully developed a novel ratiometric fluorescent probe, zt-4. Given the remarkable similarities in pathological mechanisms (including signaling pathways, regulatory nodes, and biomarkers) between osteoarthritis (OA) and DILI, we first validated the imaging performance of zt-4 in a complex inflammatory OA Model. Subsequently, we applied probe zt-4 to analyze ferroptosis-mediated DILI model at both cellular and murine levels. For the first time, our study revealed that the ferroptosis pathway dynamically regulates ONOO- levels in DILI, elucidating its molecular mechanism. These findings provide new theoretical foundations and intervention strategies for DILI treatment.
期刊介绍:
Nano Today is a journal dedicated to publishing influential and innovative work in the field of nanoscience and technology. It covers a wide range of subject areas including biomaterials, materials chemistry, materials science, chemistry, bioengineering, biochemistry, genetics and molecular biology, engineering, and nanotechnology. The journal considers articles that inform readers about the latest research, breakthroughs, and topical issues in these fields. It provides comprehensive coverage through a mixture of peer-reviewed articles, research news, and information on key developments. Nano Today is abstracted and indexed in Science Citation Index, Ei Compendex, Embase, Scopus, and INSPEC.