Heart failure with reduced ejection fraction (HFrEF), a condition in which the heart’s left ventricle cannot pump blood effectively, remains a major therapeutic challenge despite advances in drug therapy. Researchers at Harbin Medical University have identified a molecular mechanism that drives the pathological cardiac remodeling at the root of the disease: a splicing factor called Bclaf1 that hijacks the cell’s RNA processing machinery to overproduce a harmful protein.
The findings, published in Nature Communications, define a Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and suggest a new class of therapeutic targets for the condition.
The Mechanism
The team, led by Yang Zhang and co-senior authors Baofeng Yang, Yanjie Lu, and Zhenwei Pan at Harbin Medical University’s Department of Pharmacology, began by examining human heart tissue. In myocardium from HFrEF patients, they found that Bclaf1 (B-cell lymphoma 2-associated transcription factor 1) was significantly elevated compared to healthy hearts. The same elevation was seen in mouse models of pressure-overload-induced heart failure.
When the researchers genetically engineered mice to overexpress Bclaf1 specifically in heart muscle cells, the animals developed pathological hypertrophy (enlargement of the heart muscle) and systolic dysfunction, the hallmarks of heart failure. Conversely, when they knocked out the Bclaf1 gene or used an AAV9 viral vector to deliver a Bclaf1-targeting RNA interference construct, the mice were protected from pressure-overload-induced heart failure.
The molecular mechanism turned out to involve RNA splicing. Bclaf1 interacts directly with Srsf2 (serine/arginine-rich splicing factor 2), a protein that controls how pre-messenger RNA is processed into mature mRNA. The Bclaf1-Srsf2 complex binds to the pre-mRNA of Hand2 (heart and neural crest derivatives expressed 2) and enhances its splicing efficiency, producing more mature Hand2 mRNA and ultimately more Hand2 protein.
Hand2 is a transcription factor known to be involved in cardiac development. In the adult heart, its overproduction drives maladaptive remodeling, the same pathological hypertrophy and systolic dysfunction that characterize HFrEF.
The Therapeutic Window
The study demonstrates that intervention at multiple points in this cascade can rescue cardiac function. Knocking down Bclaf1 reduced Hand2 levels and attenuated hypertrophy. Direct inhibition of Hand2 produced similar protection. Inhibition of either target, Bclaf1 or Hand2, in established heart failure models partially reversed the pathological changes.
This is notable because HFrEF therapies have largely targeted neurohormonal pathways (beta-blockers, ACE inhibitors, aldosterone antagonists) rather than intracellular signaling or gene regulation. A target that sits upstream of the actual pathological gene expression program, at the splicing level, offers a different kind of intervention point.
What HFrEF Is
Heart failure with reduced ejection fraction affects roughly half of the roughly 6 million Americans living with heart failure. It is defined by an ejection fraction, the percentage of blood pumped out of the left ventricle with each contraction, of 40 percent or less, compared with 50 to 70 percent in a healthy heart. Patients experience shortness of breath, fatigue, fluid retention, and reduced exercise tolerance. Five-year mortality remains around 50 percent despite optimal medical therapy.
The condition is distinct from HFpEF (heart failure with preserved ejection fraction), where the heart stiffens rather than weakens. The Bclaf1 mechanism appears specific to HFrEF; whether it plays a role in HFpEF is unknown.
Caveats
The study was conducted in mice and validated using human tissue samples. The AAV9-mediated Bclaf1 knockdown is promising but has not been tested in humans. AAV9 gene therapy vectors have been used successfully for other cardiac conditions, notably, the FDA-approved Zolgensma for spinal muscular atrophy uses a related AAV9 vector, but cardiac delivery at scale presents challenges.
The study also showed Bclaf1 elevation in human HFrEF myocardium, but this is correlation, not causation. Whether Bclaf1 activation is a primary driver of the disease or a secondary response to cardiac stress cannot be determined from human tissue samples alone.
Disclosure: Based on a peer-reviewed paper in Nature Communications, 2026. DOI: 10.1038/s41467-026-75125-2. Co-first authors: Yang Zhang, Haiyu Gao, Ying Lu, Yingzi Zhang, Meng Yang. Corresponding: Zhenwei Pan, Baofeng Yang, Yanjie Lu (Harbin Medical University).