Myocardial fibrosis (MF) is a prevalent pathological hallmark at various stages of numerous cardiac disorders, and is the principal reason for the poor prognosis of chronic cardiac insufficiency [1,2]. Cardiac fibroblasts (CFs) are the primary “executors” of MF development, by secreting multiple cytokines, chemokines, and growth factors, which can be activated by a variety of stimuli (Ang II, TGF-β1 et al.) [3]. Activated CFs can proliferate, migrate, and differentiate into myofibroblasts while phenotypically expressing α-smooth muscle actin (α-SMA), eventually resulting in MF [4]. CF activation often results in cardiac conduction aberrations and impairments of cardiac systolic function and compliance; therefore, inhibition of CF activation is a crucial strategy for mitigation of MF development [5,6]. Unfortunately, there are no pharmaceutical drugs currently available which have been shown to materially attenuate MF in clinical practice, and strategies to develop novel medications for MF therapy have become a research priority.

Leonurine (LE), also known as SCM-198, is an extract from the Leonurus japonicus Houtt plant [7]. LE has been shown to possess antioxidative, anti-inflammatory, and other beneficial biological properties [[7], [8], [9]]. Long-term studies have demonstrated that LE exerts considerable beneficial therapeutic effects on cardiovascular disorders such atherosclerosis [8,10], myocardial ischemia [11,12], and myocarditis [13]. Notably, many preclinical studies have observed that MF may be effectively ameliorated by LE, indicating that LE could potentially be utilized as an anti-fibrotic drug [14,15].

Previously, our study has verified that LE effectively restrained CF activation and exerted significant cardioprotective effects against MF post myocardial infarction. miR-29a-3p was mechanistically involved in that process, and might even mediate the antifibrotic effect of LE against MF [15]. However, the specific regulatory effects exerted by LE on miR-29a-3p remain unknown. Recent investigations have revealed that p53 plays a role in anti-fibrotic processes by inhibition of the cyclin protein, and thus suppresses the proliferation of myofibroblasts [16,17]. Moreover, p53 has been observed to directly regulate miR-29 expression, indicating that p53 may serve as a crucial upstream protein for fibrogenesis mediation [18]. Based on our previous observations [15], we speculate that LE may attenuate MF through the p53/miR-29a-3p signaling pathway. In this study, we present evidence to support this hypothesis.