BMAL1–HIF2A heterodimer modulates circadian variations of myocardial injury

Wei Ruan (), Tao Li, In Hyuk Bang, Jaewoong Lee, Wankun Deng, Xinxin Ma, Cong Luo, Fang Du, Seung-Hee Yoo, Boyun Kim, Jiwen Li, Xiaoyi Yuan, Katherine Figarella, Yu A. An, Yin-Ying Wang, Yafen Liang, Matthew DeBerge, Dongze Zhang, Zhen Zhou, Yanyu Wang, Joshua M. Gorham, Jonathan G. Seidman, Christine E. Seidman, Sary F. Aranki, Ragini Nair, Lei Li, Jagat Narula, Zhongming Zhao, Alemayehu A. Gorfe, Jochen D. Muehlschlegel, Kuang-Lei Tsai () and Holger K. Eltzschig ()
Additional contact information
Wei Ruan: McGovern Medical School
Tao Li: McGovern Medical School
In Hyuk Bang: McGovern Medical School
Jaewoong Lee: Yale University School of Medicine
Wankun Deng: The University of Texas Health Science Center at Houston
Xinxin Ma: McGovern Medical School
Cong Luo: McGovern Medical School
Fang Du: McGovern Medical School
Seung-Hee Yoo: McGovern Medical School
Boyun Kim: McGovern Medical School
Jiwen Li: McGovern Medical School
Xiaoyi Yuan: McGovern Medical School
Katherine Figarella: McGovern Medical School
Yu A. An: McGovern Medical School
Yin-Ying Wang: The University of Texas Health Science Center at Houston
Yafen Liang: McGovern Medical School
Matthew DeBerge: McGovern Medical School
Dongze Zhang: McGovern Medical School
Zhen Zhou: McGovern Medical School
Yanyu Wang: McGovern Medical School
Joshua M. Gorham: Harvard Medical School
Jonathan G. Seidman: Harvard Medical School
Christine E. Seidman: Harvard Medical School
Sary F. Aranki: Harvard Medical School
Ragini Nair: McGovern Medical School
Lei Li: Shenzhen Bay Laboratory
Jagat Narula: Memorial Hermann Hospital
Zhongming Zhao: The University of Texas Health Science Center at Houston
Alemayehu A. Gorfe: McGovern Medical School
Jochen D. Muehlschlegel: Johns Hopkins University School of Medicine
Kuang-Lei Tsai: McGovern Medical School
Holger K. Eltzschig: McGovern Medical School

Nature, 2025, vol. 641, issue 8064, 1017-1028

Abstract: Abstract Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2–7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17–11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner—hypoxia-inducible factor 2 alpha (HIF2A)12–16—in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1–HIF2A–DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)16,17 as a rhythmic target of the BMAL1–HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1–HIF2A–AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway’s circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.

Date: 2025
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DOI: 10.1038/s41586-025-08898-z

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