As a major worldwide health concern, heart failure (HF) impacts an estimated 40 million individuals across the world [1]. The initiation of HF is significantly influenced by the activation of the renin-angiotensin system (RAS), with the process being primarily mediated by angiotensin II (Ang II) [2]. A cornerstone of HF pharmacotherapy is the utilization of RAS inhibitors (RASi), encompassing angiotensin receptor blockers and angiotensin-converting enzyme inhibitors [3]. By suppressing RAS signaling, these inhibitors have demonstrated their effectiveness in averting myocardial hypertrophy and fibrosis [4]. Regrettably, while RASi exhibits promise, it falls short of fully reversing HF in clinical scenarios [4]. Consequently, there is an urgent requirement to explore novel drug candidates and therapeutic targets that address the enduring cardiac damage caused by chronic cardiac injuries induced by Ang II.

The initiation of inflammatory processes plays pivotal roles in the advancement of HF [5]. There is mounting evidence that Ang II stimulates several signaling pathways in endothelial cells, cardiac fibroblasts, and cardiomyocytes, among other cells, directly leading to cardiac inflammation, cardiac dysfunction, and maladaptive cardiac remodeling. Our group's recent research suggests that the inflammatory response triggered by Ang II contributes to the advancement of cardiac remodeling induced by Ang II [6], [7]. The precise targeting of inflammation emerges as a highly promising therapeutic avenue for HF induced by Ang II [8].

There is a growing trend towards a heightened focus on the exploration of natural substances for both the avoidance and management of cardiovascular disorders. Carnosol (Car), primarily derived from the natural plant (Salvia carnosa), has demonstrated multifaceted bioactive properties, encompassing notable anti-inflammatory effects [9], [10], antitumors [11], and antioxidants [12]. An investigation has demonstrated the robust anti-inflammatory attributes of Car, providing defense against rheumatoid arthritis by reducing the activity of the MAPK and TLR4/NF-κB signaling pathways [13]. Car was also shown to ameliorate LPS-induced inflammation in cardiomyocytes by diminishing the gene expression and protein levels of inflammatory factors [14]. Nonetheless, the function and mechanism of Car in cardiac hypertrophy progression remained poorly understood. Considering that chronic inflammation significantly contributes to Ang II-induced HF, we postulated that treatment with Car could potentially confer protection against hypertensive HF through regulating the inflammation response.

This study aimed to explore Car's possible cardioprotective benefits and underlying mechanisms of Car against hypertensive HF induced by Ang II. We confirmed its protective effect against inflammation and hypertrophy through both in vitro and in vivo experiments. RNA-Seq was used to explore the signaling pathway that is regulated by Car. Finally, the molecular target of Car was determined by pull-down experiments and surface plasmon resonance (SPR). Our research illustrated Car as a promising option for treating hypertensive HF.