Heart failure (HF) is characterized by abnormal pumping function of the heart and decreased efficiency of the circulatory system (Conrad et al., 2018). At the end stage of multiple cardiovascular diseases, the decompensated heart is unable to eject or hold blood under physiological pressure, eventually leading to functional limitation and HF (Bocchi et al., 2005). In recent years, the number of HF patients in the world has continued to increase, reaching 64.3 million by 2017. There are significant geographical and socio-demographic differences in the levels and trends of HF burden (Bragazzi et al., 2021), suggesting that the intervention strategies of HF process still need to be improved.

Accumulating evidence has shown that non-coding RNAs, including microRNAs (miRNAs) and circRNAs, can play critical roles in cardiovascular disease development (Montgomery et al., 2011; Wahlquist et al., 2014; Zhang et al., 2022). MicroRNAs are well known as negative regulators of gene expression (Ambros, 2004; Bartel, 2004). Circular RNAs (circRNAs) are a valuable class of non-coding RNAs with a covalent closed-loop structure (Sanger et al., 1976), that are more stable than linear RNA, conserved among species (Memczak et al., 2013), and play roles as miRNA sponges in regulation of multiple disease processes (Zheng et al., 2016; Piwecka et al., 2017; Kristensen et al., 2018). Given the hypothesis of competitive endogenous ribonucleic acid (ceRNA) network (Salmena et al., 2011), circRNAs may participate in the pathogenesis of the cardiovascular system, such as cardiomyopathy (Wang et al., 2016) and HF (Du et al., 2021). For instance, circRNA wwp1 exerts functions by targeting miR-23a and ANF on isoproterenol-induced cardiac hypertrophy (Wang et al., 2022; Wu et al., 2022). These studies suggest that further elucidation of the underlying mechanisms by which circRNAs regulate HF progression would be beneficial to the design of therapeutic strategies (Li et al., 2020; Wu et al., 2022).

Biomarker identification for complex diseases like heart failure remains challenging, despite advances in high-throughput sequencing technologies (Halliday et al., 2019). In this study, we identify the functional molecule, circular RNA CHRC, by establishing a competitive endogenous RNA regulatory network. We further elucidate that circRNA CHRC plays a pivotal role in cardiac hypertrophy by targeting the miR-431-5p/Klf15 core signaling axis, both in vivo and in vitro. Furthermore, circRNA CHRC enhances the expression of Klf15 by competitively interacting with miR-431-5p during the pathological progression, thereby mitigating cardiac hypertrophy and decelerating HF development.