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BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia–reperfusion injury via BRD4–YY1–NCOA4 axis disruption and ferroptosis inhibition
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DOI：10.1016/j.apsb.2026.07.043.png)
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Abstract
En 中文
Myocardial ischemia/reperfusion injury (MI/RI) remains a major barrier to ischemic heart disease treatment, as reperfusion therapies often exacerbate cardiac damage. Bromodomain-containing protein 4 (BRD4) is a key epigenetic target in cardiovascular diseases, but pan-BRD4 inhibitors cause severe off-target toxicity by disrupting basal bromodomain 1 (BD1) function, highlighting the need for BD2-selective agents. This study aimed to develop a BD2-selective BRD4 inhibitor and clarify its mechanism. ZX29 was developed via virtual screening of 100,000 compounds and structure-based optimization, exhibiting potent BRD4 binding with an IC50 of 0.27 ± 0.03 μmol/L and Kd of 1.68 μmol/L, outperforming clinical agent RVX-208. ZX29 specifically binds BRD4 BD2 via H437/V439 residues. In murine MI/RI models, oral ZX29 significantly improved cardiac systolic and diastolic function, reduced myocardial infarct size, and mitigated lipid peroxidation. Mechanistically, ZX29 disrupted the BRD4–Yin Yang 1 (YY1) interaction and inhibited the nuclear receptor coactivator 4 (NCOA4)–ferritin heavy chain 1 (FTH1) degradation axis, suppressing lysosomal ferrous iron release and ferroptosis. Moreover, ZX29 preserved mitochondrial function by maintaining mitochondrial membrane potential and boosting ATP production. Ultimately, this study validates selective BRD4 BD2 inhibition as a safe and effective therapeutic strategy for MI/RI and establishes ZX29 as a viable clinical candidate.
Keywords:
BRD4
YY1
Ferroptosis
Mitochondrial dysfunction
Lipid peroxidation
Epigenetic regulation
Cardiac fibrosis
Myocardial injury
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