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Targeted degradation of proteins, especially those regarded as undruggable or difficult to drug, attracts wide attention to develop novel therapeutic strategies. Glutathione peroxidase 4 (GPX4), the key enzyme regulating ferroptosis, is currently a target with just covalent inhibitors. Here, we developed a targeted photolysis approach and achieved efficient degradation of GPX4. The photodegradation-targeting chimeras (PDTACs) were synthesized by conjugating a clinically approved photosensitizer (verteporfin) to noninhibitory GPX4-targeting peptides. These chimeras selectively degraded the target protein in both cell lysates and living cells upon red-light irradiation. The targeted photolysis of GPX4 resulted in dominant ferroptotic cell death in malignant cancer cells. Moreover, the dying cells resulting from the PDTACs exhibited potent immunogenicity in vitro and efficiently elicited antitumor immunity in vivo. Our approach therefore provides a novel method to induce GPX4 dysfunction based on noncovalent binding and specifically trigger immunogenic ferroptosis, which may boost the application of ferroptosis in cancer immunotherapy.

In this study, 167 land parcels of downtown Shanghai, China, were used to investigate the relationship between parcel-level land use/land cover (LULC) components and associated summertime intra-surface urban heat island (SUHI) effect, and further analyze the potential of mitigating summertime intra-SUHI effect through the optimized LULC components, by integrating a thermal sharpening method combining the Landsat-8 thermal band 10 data and high-resolution Quickbird image, statistical analysis, and nonlinear programming with constraints. The results show the remarkable variations in intra-surface urban heat island (SUHI) effect, which was measured with the mean parcel-level blackbody sensible heat flux in kW per ha (Mean_pc_BBF). Through measuring the relative importance of each specific predictor in terms of their contributions to changing Mean_pc_BBF, the influence of parcel-level LULC components on excess surface flux of heat energy to the atmosphere was estimated using the partial least square regression (PLSR) model. Analysis of the present and optimized parcel-level LULC components and their contribution to the associated Mean_pc_BBF were comparable between land parcels with varying sizes. Furthermore, focusing on the gap between the present and ideally optimized area proportions of parcel-level LULC components towards minimizing the Mean_pc_BBF, the uncertainties arising from the datasets and methods, as well as the implications for sustainable land development and mitigating the UHI effect were discussed.

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