{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:10:12Z","timestamp":1789063812973,"version":"build-2803163510"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERR\u03b1 (estrogen-related receptor \u03b1) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERR\u03b1. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>ERR\u03b1 expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERR\u03b1 reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERR\u03b1 overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERR\u03b1 knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERR\u03b1 agonist. Formononetin enhanced ERR\u03b1 transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERR\u03b1 occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERR\u03b1\/PGC-1\u03b1 (peroxisome proliferator-activated receptor \u03b3 coactivator-1\u03b1) complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>ERR\u03b1 downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERR\u03b1 activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.126.329042","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T09:00:11Z","timestamp":1786525211000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Natural ERR\u03b1 Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1370-490X","authenticated-orcid":true,"given":"Xiaoping","family":"Wang","sequence":"first","affiliation":[{"name":"School of Chinese Medicine, Beijing University of Chinese Medicine (X.W., G.L., Y. Wei, W.L., Y.C., W.W., Y. Wang)."},{"name":"Institute of Basic Medical Sciences &amp; School of Basic Medicine, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing (X.W., Z.Y., Q.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanjing","family":"Ling","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Beijing University of Chinese Medicine (X.W., G.L., Y. Wei, W.L., Y.C., W.W., Y. Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Beijing University of Chinese Medicine (X.W., G.L., Y. Wei, W.L., Y.C., W.W., Y. Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-1339","authenticated-orcid":true,"given":"Weili","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Beijing University of Chinese Medicine (X.W., G.L., Y. Wei, W.L., Y.C., W.W., Y. Wang)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3522-9257","authenticated-orcid":true,"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Diabetes Institute, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, China (Y.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9424-0720","authenticated-orcid":true,"given":"Ziyi","family":"Yin","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences &amp; School of Basic Medicine, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing (X.W., Z.Y., Q.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, China (K.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7415-6616","authenticated-orcid":true,"given":"Qian","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences &amp; School of Basic Medicine, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing (X.W., Z.Y., Q.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Breast Disease, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing (L.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Beijing University of Chinese Medicine (X.W., G.L., Y. 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