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We report esterase\u2010activated hydropersulfide (RSSH) donors, alkyl sulfenyl thiocarbonate (\n                    <jats:bold>AST\u20102<\/jats:bold>\n                    ), and acetoxy perthiocarbamate (\n                    <jats:bold>APT\u20101<\/jats:bold>\n                    ), together with their mitochondria\u2010targeted analogs,\n                    <jats:bold>AST\u20102\u2010TPP<\/jats:bold>\n                    and\n                    <jats:bold>APT\u20101\u2010TPP<\/jats:bold>\n                    , which bear a triphenylphosphonium (TPP\u207a) moiety. These compounds release RSSH upon esterase activation with tunable half\u2010lives (20\u2013125\u00a0min in PBS, pH 7.4). LC\u2013MS\/MS analysis revealed that\n                    <jats:bold>APT\u20101<\/jats:bold>\n                    elevates hydropersulfide levels in the cytosol of H9c2 cardiomyoblasts, whereas its mitochondrial analog,\n                    <jats:bold>APT\u20101\u2010TPP<\/jats:bold>\n                    , increases levels in mitochondria. All donors attenuated DOX\u2010induced toxicity in H9c2 cells, but in cancer cell lines (HepG2, MDA\u2010MB\u2010468, MCF\u20107),\n                    <jats:bold>APT\u20101<\/jats:bold>\n                    did not blunt DOX cytotoxicity and\n                    <jats:bold>APT\u20101\u2010TPP<\/jats:bold>\n                    synergistically enhanced its activity. Mechanistic studies revealed that both\n                    <jats:bold>APT\u20101<\/jats:bold>\n                    and\n                    <jats:bold>APT\u20101\u2010TPP<\/jats:bold>\n                    rescue DOX\u2010induced mitochondrial membrane depolarization and ATP depletion in H9c2 cells but not in HepG2 cells. Further characterization indicated that cancer cells exhibit higher basal sulfane sulfur levels and mitochondrial membrane potentials compared to H9c2 cells, suggesting that divergent redox environments may underlie these contrasting effects. Collectively, these findings demonstrate that redox heterogeneity between cardiac and cancer cells can be exploited to develop cardioprotective interventions that preserve or enhance DOX's anticancer efficacy.\n                  <\/jats:p>","DOI":"10.1002\/anie.202521645","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:58:00Z","timestamp":1765598280000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Esterase\u2010Responsive Mitochondria\u2010Targeted Hydropersulfide Donors Mitigate Doxorubicin Cardiotoxicity While Preserving Anticancer Activity"],"prefix":"10.1002","volume":"65","author":[{"given":"Jinjing","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Lamar","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaire R.","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinayak S.","family":"Khodade","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 USA"},{"name":"Smidt Heart Institute Department of Cardiac Surgery Cedars\u2010Sinai Medical Center  Los Angeles CA 90048 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4277-3533","authenticated-orcid":false,"given":"John P.","family":"Toscano","sequence":"additional","affiliation":[{"name":"Department of Chemistry Johns Hopkins University  Baltimore Maryland 21210 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