High-Throughput Screening of Antioxidant Drug Candidates from Natural Antioxidants with a “Zero” Intrinsic Fluorescence Peroxynitrite Sensing Precursor

The fluorescence high-throughput screening method is of importance for new antioxidant drug candidate discovery for the treatment of serious hepatorenal syndrome, which displayed an obvious upregulated peroxynitrite level. However, most of the current ONOO^– probes possessed incomplete fluorescence quenching efficiency, which can result in non-negligible probe inherent fluorescence. Hence, we utilized the probe conjugated structure disruption strategy to construct hydrogenation phosphorus-substituted rhodamine (H–PRh) with “zero” probe inherent fluorescence character. Based on the precursor, a series of natural products were screened for identifying antioxidant drug candidates. Luteolin was screened out by activating the Sirt1-Nrf2-HO-1 signaling pathway to regulate the accumulation of ONOO^– in the hepatorenal syndrome. Overall, the “zero” probe inherent fluorescence ONOO^– sensor constructed here applies for a promising and versatile toolbox for illuminating the ONOO^–-related pathological process in the hepatorenal syndrome. Besides, this strategy of constructing highly sensitive sensors could serve as a valuable reference for further fluorescent probes.