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While photochemical strategies offer spatiotemporal control, most current methods rely on exogenous catalysts, complicating purification processes. Furthermore, the structural diversity of accessible conjugates remains limited. Here, we report an additive\/catalyst\u2010free, visible\u2010light\u2010driven platform for divergent cysteine modification via indole isocyanide photochemistry. This strategy eliminates the need for external additives or photocatalysts, ensuring excellent biocompatibility and operational simplicity. A key practical advantage of this method is its compatibility with both solution\u2010phase and solid\u2010phase reaction systems, offering unmatched flexibility for diverse experimental setups. By leveraging the tunable structure of indole isocyanides, this photoreaction readily generates a diverse array of indole\u2010fused or indole\u2010spiro aza\u2010cycles at cysteine residues. We demonstrate broad utility of this method, ranging from site\u2010specific modification of peptides and proteins to the synthesis of cyclic peptides and the assembly of proteolysis\u2010targeting chimeras (PROTACs). Moreover, a chemical proteomics profiling employing indole isocyanide\u2010based photoprobe achieved selective modification of C77 within the therapeutic phosphatase target PPP5C. This interaction revealed a novel druggable pocket at the TPR\u2013catalytic domain interface, uncovering a previously unknown allosteric inhibition strategy. Collectively, this work establishes a robust, versatile platform for advancing therapeutic discovery and chemical biology.<\/jats:p>","DOI":"10.1002\/anie.202524506","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T07:29:17Z","timestamp":1777015757000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Catalyst\u2010Free, Divergent Cysteine Modification via Indole Isocyanide Photochemistry"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8578-6780","authenticated-orcid":false,"given":"Han","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan China"},{"name":"Henan Key Laboratory of Precision Clinical Pharmacy The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan 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