{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:25:12Z","timestamp":1787041512249,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Forschung, Technologie und Raumfahrt","doi-asserted-by":"publisher","award":["01KC2006B"],"award-info":[{"award-number":["01KC2006B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 1550"],"award-info":[{"award-number":["CRC 1550"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LE3570\/2\u20131"],"award-info":[{"award-number":["LE3570\/2\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["LE3570\/3\u20131"],"award-info":[{"award-number":["LE3570\/3\u20131"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>Myeloid cell leukaemia\u20101 (MCL\u20101) is an essential anti\u2010apoptotic protein and a promising therapeutic target in oncology. Early clinical studies of MCL\u20101 inhibitors reported unexpected elevations in cardiac troponin, raising concerns about potential cardiotoxicity. Conventional murine models may incompletely capture human\u2010relevant cardiac effects due to species\u2010specific differences in MCL\u20101 pharmacology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>We investigated the cardiac effects of the selective MCL\u20101 inhibitor MIK665 in a humanised MCL\u20101 mouse model. Animals were treated once weekly and assessed for cardiac biomarkers, left ventricular function by echocardiography, and myocardial transcriptomic changes at peak treatment (Day 14) and after treatment cessation (Day 21). Bulk RNA sequencing was used to characterise differential gene expression, pathway enrichment and higher\u2010order transcriptional modules.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>MIK665 treatment induced a time\u2010dependent increase in circulating cardiac troponin T without detectable impairment of left ventricular systolic function. Transcriptomic analysis revealed coordinated suppression of mitochondrial and contractile gene programmes during treatment, accompanied by activation of stress\u2010 and immune\u2010associated pathways. After treatment cessation, cardiac troponin levels declined and the myocardial transcriptome shifted towards a distinct recovery\u2010associated profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Pharmacological MCL\u20101 inhibition induced a cardiac biomarker and transcriptional stress response characterised by troponin release and dynamic myocardial transcriptomic remodelling. Additional functional and histological analyses did not reveal overt systolic dysfunction, strain\u2010detectable impairment, or increased fibrotic remodelling. These alterations are consistent with a largely reversible cardiac stress response rather than overt structural or functional cardiotoxicity. These findings support the use of refined, humanised preclinical models to improve translational cardiac safety assessment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70624","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:41:59Z","timestamp":1787038919000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MCL\u20101 inhibition triggers a largely reversible cardiac stress signature in a humanised mouse model"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3085-1282","authenticated-orcid":false,"given":"Markus B.","family":"Heckmann","sequence":"first","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsanett","family":"Papdi","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils J.","family":"Strauch","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-7536","authenticated-orcid":false,"given":"Daniel","family":"Finke","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4181-6922","authenticated-orcid":false,"given":"Marc\u2010Steffen","family":"Raab","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Rheumatology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-5194","authenticated-orcid":false,"given":"Antje","family":"Blank","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5077-8580","authenticated-orcid":false,"given":"Lorenz H.","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology Heidelberg University Hospital  Heidelberg Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim  Germany"},{"name":"Deutsches Krebsforschungszentrum, Heidelberg (DKFZ)  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"S1","article-title":"The concise guide to pharmacology 2025\/26: Introduction and other protein targets","volume":"182","author":"Alexander S. 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