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Here we report a semi\u2010rationally engineered P450 variant, MB4, that enables highly selective C7\u03b2 hydroxylation of 18\u03b2\u2010glycyrrhetinic acid, achieving C\u2013H activation on the B\u2010ring with &gt; 99% regioselectivity. Protein crystallography and computational studies revealed that the reshaped active pocket of MB4 disrupts the native 1,5\u2010hydrogen atom transfer (1,5\u2010HAT) relay oxidation, thereby redirecting the regioselectivity exclusively to the B\u2010ring C7 position. The synthetic utility of MB4 was demonstrated through substrate scope investigation, large\u2010scale preparation, and a chemoenzymatic synthesis platform that generated a library of previously inaccessible B\u2010ring\u2010modified PT derivatives. Biological evaluation showed that several C7\u2010acylated derivatives exhibited antiproliferative activity (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a00.31\u20135.04\u00a0\u00b5M) by triggering caspase\u20103\u2010dependent apoptosis and inducing G2\/M\u2010phase arrest. This work provides a promising blueprint for reprogramming P450 selectivity for late\u2010stage C\u2013H functionalization of polycyclic natural products.\n                  <\/jats:p>","DOI":"10.1002\/anie.2096522","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:15:07Z","timestamp":1788948907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Redirecting Regioselectivity in Cytochrome P450 ApPT for B\u2010Ring Functionalization of Pentacyclic Triterpenoids"],"prefix":"10.1002","author":[{"given":"Xiaowei","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Coordination Chemistry Jiangsu Key Laboratory of Advanced Organic Materials Chemistry and Biomedicine Innovation Center School of Chemistry Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingming","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing Jiangsu 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2943-1299","authenticated-orcid":false,"given":"Liao\u2010Bin","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing Jiangsu 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