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In this study, a glutathione (GSH)-responsive nano-photosensitizer, based on the chlorquinaldol (CQD)-loaded iron-containing nanorod composed of meso-tetra (4-carboxyphenyl) porphyrin (TCPP), was prepared to serve as the laser-ignited ferroptosis sensitizer to improve the tumoricidal effect of PDT. In the tumor microenvironment (TME) with elevated GSH levels, therapeutic cargos and ferrous ions are released and are accompanied by the degradation of the nano-photosensitizer and GSH exhaustion. This not only increases liable iron pool (LIP) accumulation by the released ferrous ions but also decreases glutathione peroxidase 4 (GPX4) activity by GSH exhaustion. Simultaneously, GSH exhaustion disrupts intracellular redox homeostasis, heightening NIR light irradiation-triggered photosensitive oxidative stress. Moreover, the released CQD elevates the level of intracellular reactive oxygen species (ROS), enabling the nanorods to gain an oxygen radical generation ability and enhancing the photosensitive oxidative therapeutic efficacy. Strikingly, CQD exacerbates the downregulation of GPX4 expression to promote the accumulation of lipid peroxides. Therefore, we herald a new paradigm for synergistically potentiating PDT based on the \u201call-in-one\u201d nano-photosensitizer through the multi-pronged upregulation of ferroptosis sensitivity.<\/jats:p>","DOI":"10.3390\/antiox14040407","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T13:36:49Z","timestamp":1743169009000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["GSH-Responsive Nano-Photosensitizer for Potentiating Photodynamic Therapy Through Multi-Pronged Synergistic Upregulation of Ferroptosis Sensitivity"],"prefix":"10.3390","volume":"14","author":[{"given":"Yunong","family":"Ma","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Feng","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peilin","family":"Tian","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayang","family":"Luo","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyao","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0317-2037","authenticated-orcid":false,"given":"Jiaxing","family":"Song","sequence":"additional","affiliation":[{"name":"Cell and Immunology Laboratory, Medical Research Centre, School of Life Sciences and Medical Engineering, Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6074-885X","authenticated-orcid":false,"given":"Cuixia","family":"Lu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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