biostudies-literatureTan JShanghai Basic Research Pioneer ProjectChinese Academy of SciencesShanghai Key Laboratory of Aging StudiesNational Natural Science Foundation of ChinaShanghai Municipal Youth Science and Technology Star ProjectYouth Innovation Promotion Association of the Chinese Academy of Sciences45774-45784https://www.ebi.ac.uk/biostudies/studies/S-EPMC12874534biostudies-literatureUnknown147(49)Radical reactions offer transformative potential in biological contexts but remain constrained by poor selectivity and off-target reactivity. We address these limitations through visible-light photocatalytic generation of diaryl ketyl radicals from benzophenones. This strategy circumvents traditional UV excitation pathways by suppressing triplet diradical formation─which drives nonspecific [2 + 2] cycloadditions and H atom abstraction─in favor of bioorthogonal radical-radical coupling. Our platform enables precise live-cell protein labeling with minimal cytotoxicity, including in sensitive primary neuronal cultures, and achieves site-specific modification via genetically incorporated benzophenone-based unnatural amino acids Bpa. The spatial selectivity of this approach exceeds conventionalJournal of the American Chemical SocietyBioorthogonal Photocatalytic Protein Labeling and Cross-Linking Enabled by Stabilized Ketyl Radicals.PMC12874534XDB106000022277133202326619DZ226040022337005Che QQi LLi YHao KWang RTan JZhang YChen YXie SYuan YfalseBioorthogonal Photocatalytic Protein Labeling and Cross-Linking Enabled by Stabilized Ketyl Radicals.Radical reactions offer transformative potential in biological contexts but remain constrained by poor selectivity and off-target reactivity. We address these limitations through visible-light photocatalytic generation of diaryl ketyl radicals from benzophenones. This strategy circumvents traditional UV excitation pathways by suppressing triplet diradical formation─which drives nonspecific [2 + 2] cycloadditions and H atom abstraction─in favor of bioorthogonal radical-radical coupling. Our platform enables precise live-cell protein labeling with minimal cytotoxicity, including in sensitive primary neuronal cultures, and achieves site-specific modification via genetically incorporated benzophenone-based unnatural amino acids Bpa. The spatial selectivity of this approach exceeds conventional2025-01-01T00:00:00Z2025 Dec2026-07-15T09:12:24.135Z2026-07-02T03:08:52.284ZS-EPMC128745344131506510.1021/jacs.5c18652