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Using high\u2010throughput screening, the approved all\u2010trans retinoic acid (ATRA) is identified that exhibit high selectivity in killing HMA\u2010resistant AML cells compared to parental cells. Mechanistically, HMA\u2010resistant cells are overloaded with DNA hypomethylation\u2010associated endogenous viral double\u2010stranded RNA (dsRNA) which, however, fails to trigger an anticancer interferon (IFN) immune response due to downregulation of dsRNA sensor retinoic acid\u2010inducible gene I (RIG\u2010I). ATRA compensates for RIG\u2010I expression, thereby re\u2010triggering IFN response and potently inhibiting HMA\u2010resistant AML cell lines, xenograft mice, and patient\u2010derived primary cells. A library of potential RIG\u2010I\u2010inducing compounds is rationally constructed and screened, in which the approved M3 AML treatment drug tamibarotene (TAM) exhibits strikingly 28036\u2010fold selectivity and 779 p\n                    <jats:sc>m<\/jats:sc>\n                    IC\n                    <jats:sub>50<\/jats:sub>\n                    in killing HMA\u2010resistant AML cells. ATRA and TAM do not selectively inhibit p53\u2010mutant cancer cells. Together, this study uncovers a common resistance mechanism in HMA\u2010treated AML patients and, in addition, provides highly potent and selective agents that can overcome resistance through re\u2010triggering IFN anticancer immune response.\n                  <\/jats:p>","DOI":"10.1002\/advs.202414477","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T07:24:52Z","timestamp":1750922692000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RIG\u2010I\u2010Inducing Small Molecules Potently Inhibit HMA\u2010Resistant AML Through Igniting the Overloaded dsRNA Arsenal"],"prefix":"10.1002","volume":"12","author":[{"given":"Xueqin","family":"Chen","sequence":"first","affiliation":[{"name":"Shanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at Shanghai Ruijin Hospital Shanghai Jiao Tong University School of 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