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We show that ALDH\u2010mediated restoration of NADH\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    balance can buffer photoredox\u2010induced NADH depletion, providing a design rationale for coupling enzyme inhibition with photoredox catalysis. To counteract this redox\u2010buffering process, we introduce an enzymatic\u2013photocatalytic strategy, termed E\u2013PC, that integrates ALDH inhibition with NIR\u2010driven photocatalytic NADH oxidation within a single molecular construct. A small\u2010molecule conjugate,\n                    <jats:bold>DE\u2010Et<\/jats:bold>\n                    , was constructed by covalently linking DEAB, which can inhibit ALDH, to a near\u2010infrared (NIR)\u2013active Nile Blue Sulfide\u2013derived photocatalyst (NBS) through a ROS\u2010cleavable thioacetal linker. Upon NIR irradiation,\n                    <jats:bold>DE\u2010Et<\/jats:bold>\n                    releases DEAB while catalytically oxidizing intracellular NADH through single\u2010electron transfer, thereby attenuating ALDH\u2010mediated redox restoration and sustaining NADH\/NAD\n                    <jats:sup>+<\/jats:sup>\n                    imbalance. This dual action compromises mitochondrial ATP production and activates caspase\u20103\/GSDME\u2010dependent pyroptosis. In stemness\u2010enriched tumor models,\n                    <jats:bold>DE\u2010Et<\/jats:bold>\n                    suppresses ALDH activity, clonogenic growth, spheroid integrity, and tumor growth in vivo. Local photoactivation further promotes systemic antitumor immune responses, consistent with immunogenic pyroptotic cell death. E\u2013PC thus establishes a chemical strategy for light\u2010activated co\u2010delivery of photoredox catalysis and inhibition of a tumor\u2010overexpressed enzyme, converting an adaptive enzymatic buffer into a therapeutic vulnerability.\n                  <\/jats:p>","DOI":"10.1002\/anie.5856873","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:58:47Z","timestamp":1787979527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ALDH Inhibition\u2010Primed Photocatalysis Disrupts Cancer Stemness Plasticity"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7752-9270","authenticated-orcid":false,"given":"Yujin","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemistry Korea University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankun","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Nanjing University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry Korea University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7341-6953","authenticated-orcid":false,"given":"Rongrong","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-9909","authenticated-orcid":false,"given":"Hyeonji","family":"Rha","sequence":"additional","affiliation":[{"name":"Department of Chemistry Korea University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0240-1033","authenticated-orcid":false,"given":"Shumeng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Nanjing University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4801-6052","authenticated-orcid":false,"given":"Kippeum","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Korea University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjie","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Life and Health Sciences Hainan Province Key Laboratory of One Health Collaborative Innovation Center of Life and Health Hainan University  Haikou PR 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