{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:55:58Z","timestamp":1790916958153,"version":"4.1.0"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Doxorubicin (DOX) is the most widely used anthracycline in hematologic and solid tumors, whose clinical utility is constrained by dose-dependent cumulative cardiotoxicity that can progress to chronic heart failure. Although previously attributed to overt cardiomyocyte loss, emerging evidence indicates that stress-induced premature senescence (SIPS) constitutes the dominant mechanism of chronic cardiotoxicity at clinically relevant concentrations. SIPS is defined by permanent cell cycle arrest, activation of the p53\/p21 and p16\/Rb tumor suppressor axes, mitochondrial dysfunction, and a senescence-associated secretory phenotype (SASP) that sustains a pro-inflammatory myocardial milieu. Nevertheless, the post-transcriptional mechanisms that govern this process remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The post-transcriptional regulation of DOX-induced SIPS was evaluated\n                      <jats:italic>in vitro<\/jats:italic>\n                      using neonatal rat ventricular myocytes (NRVMs) exposed to sublethal DOX (0.1 \u03bcM) with or without prophylactic miR-15b restoration via a synthetic mimetic to assess the p53\/p21, p16, SASP, lysosomal, and mitochondrial responses.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , a chronic cardiotoxicity model was established in female C57BL\/6 mice receiving a cumulative dose of 30 mg\/kg DOX to analyze myocardial miR-15b suppression, SIPS markers, and SASP profiles across survival cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sublethal DOX treatment (0.1 \u03bcM) suppressed miR-15b expression by approximately 50% in NRVMs, resulting in post-transcriptional derepression of its mitochondrial target, SIRT4. This miR-15b loss triggered a multiparametric SIPS phenotype encompassing accumulation of \u03b3H2AX foci, p53\/p21 and p16 activation, SASP induction (IL-6, IL-1\u03b2, Mcp-1 and Mmp13), lysosomal dysfunction (increased SA-\u03b2-Gal staining) and mitochondrial dysfunction. Prophylactic restoration of miR-15b via a synthetic mimetic selectively attenuated the p53\/p21 axis, genomic damage foci, lysosomal dysfunction, mitochondrial dysfunction and SASP (IL-6 and IL-1\u03b2), without rescuing the p16\/Rb pathway. In the female C57BL\/6 chronic cardiotoxicity model, the cohort spontaneously stratified into animals completing the protocol (ND; 67%) and a premature death subgroup (PD; 33%). The PD subgroup exhibited the most profound myocardial miR-15b suppression and greater accumulation of SIPS markers, including \u03b3H2AX, p16, and reduced Lamin B. Notably, the SASP displayed distinct qualitative profiles between PD and ND animals, suggesting that SASP composition, rather than magnitude alone, determines the cardiotoxic outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Collectively, these findings position miR-15b as a key post-transcriptional regulator of DOX-induced SIPS in the cardiomyocyte, whose sustained loss associates with cardiotoxicity severity\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1924670","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:41:33Z","timestamp":1790916093000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["microRNA-15b modulates stress-induced premature senescence in chronic doxorubicin cardiomyopathy"],"prefix":"10.3389","volume":"17","author":[{"given":"Georthan","family":"Mancilla","sequence":"first","affiliation":[{"name":"NIFBF, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile","place":["Santiago, Chile"]},{"name":"Cardiovascular Signaling Laboratory, Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile","place":["Santiago de Chile, Chile"]},{"name":"Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Cat\u00f3lica de Chile and Universidad de Chile","place":["Santiago de Chile, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Quiroga","sequence":"additional","affiliation":[{"name":"Cardiovascular Signaling Laboratory, Division of Cardiovascular Diseases, Faculty of Medicine, Pontificia Universidad Cat\u00f3lica de Chile","place":["Santiago de Chile, 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