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Here, we report a target\u2010guided strategy for the development of diazo\u2010based photoswitchable inhibitors of human 15\u2010lipoxygenase\u20101 (15\u2010LOX\u20101), a key enzyme in inflammatory signaling, ferroptosis, and cancer. Guided by the structural features of known ligands, we developed three complementary photoswitch classes: reversible azobenzenes (ABs), azo\u2010heteroarenes (HAs), and covalent azo\u2010bis\u2010alkynes (BAs). These compounds exhibit efficient\u00a0\n                    <jats:italic>E<\/jats:italic>\n                    \/\n                    <jats:italic>Z<\/jats:italic>\n                    \u00a0photoisomerization and high bistability, supported by single\u2010crystal x\u2010ray diffraction and density functional theory calculations. Enzymatic inhibitory and kinetic studies revealed distinct activity and selectivity profiles within the tested substrates\/isoenzyme: AB and HA derivatives function as\u00a0\n                    <jats:italic>E<\/jats:italic>\n                    \u2010ON\/Z\u2010OFF inhibitors, whereas BA derivatives display\u00a0\n                    <jats:italic>Z<\/jats:italic>\n                    \u2010ON\/\n                    <jats:italic>E<\/jats:italic>\n                    \u2010OFF behavior, enabling programmable light\u2010controlled modulation. We validated 15\u2010LOX\u20101 as a therapeutic target in cellular and\u00a0in vivo\u00a0mouse models of colonic inflammation, where inhibition suppressed IL\u20108 expression. Finally, using our reversible and covalent photoswitches, we demonstrate photoisomer\u2010dependent suppression of IL\u20108. Beyond 15\u2010LOX\u20101, this work establishes a generalizable framework for the rational development of selective photoswitchable inhibitors with tunable biological outcomes.\n                  <\/jats:p>","DOI":"10.1002\/anie.3141559","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T12:03:20Z","timestamp":1782475400000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Light\u2010Controlled Modulation of 15\u2010Lipoxygenase\u20101 Regulates Intestinal Inflammatory Signaling"],"prefix":"10.1002","volume":"65","author":[{"given":"Anastasia","family":"Louka","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Crete  Heraklion Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini\u2010Eleni","family":"Kalaitzaki","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Crete  Heraklion 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