2. Academic Validation
  3. A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in cardiac fibrosis

A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in cardiac fibrosis

  • Acta Pharm Sin B. 2025 Oct;15(10):5192-5211. doi: 10.1016/j.apsb.2025.07.036.
Yuan Jiang 1 2 3,  Bowen Zhang 1 2 4,  Bo Zhang 1 2,  Xinhua Song 1 2,  Xiangyu Wang 1 2,  Wei Zeng 1 2 3,  Liyang Zuo 1 2,  Xinqi Liu 1 2,  Zheng Dong 1 2,  Wenzheng Cheng 1 2,  Yang Qiao 1 2,  Saidi Jin 1 2,  Dongni Ji 1 2,  Xiaofei Guo 1 2 4,  Rong Zhang 1 2,  Xieyang Gong 5,  Lihua Sun 1 2,  Lina Xuan 1 2,  Berezhnova Tatjana Alexandrovna 6,  Xiaoxiang Guan 1 2 7,  Mingyu Zhang 1 2,  Baofeng Yang 1 2,  Chaoqian Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 2 Department of Pharmacology, State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 3 Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 4 Institute of Clinical Pharmacy, the Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
  • 5 Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
  • 6 Department of Pharmacology of Voronezh State Medical University, Voronezh 394018, Russia.
  • 7 Institute of Clinical Pharmacy, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
PMID: 41132846 DOI: 10.1016/j.apsb.2025.07.036
Abstract

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of Histone Acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Keywords

BRPF3; CELF1; Cardiac fibrosis; Circ-CELF1; Feedback loop; Histone acetylation; KAT7; Therapeutic target.

Figures
Products