Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE₂ production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with G_αq to elicit intracellular Ca²⁺ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE₂/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.

Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin E2 (PGE2) plays a dual role in innate and adaptive immunity. Here, we found that E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell–specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. Loss of EP3 selectively reduced the cytotoxicity of the CD27+CD11b+ double positive (DP) NK subset against activated HSCs. Mechanistically, deletion of EP3 impaired the adhesion and cytotoxicity of DP NK cells toward HSCs through modulation of Itga4-VCAM1 binding. EP3 upregulated Itga4 expression in NK cells through promoting Spic nuclear translocation via PKC-mediated phosphorylation of Spic at T191. Activation of EP3 by sulprostone alleviated CCL4-induced liver fibrosis in mice. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.

Cardiac fibrosis is a common pathophysiologic process associated with numerous cardiovascular diseases, resulting in cardiac dysfunction. Cardiac fibroblasts (CFs) play an important role in the production of the extracellular matrix and are the essential cell type in a quiescent state in a healthy heart. In response to diverse pathologic stress and environmental stress, resident CFs convert to activated fibroblasts, referred to as myofibroblasts, which produce more extracellular matrix, contributing to cardiac fibrosis. Although multiple molecular mechanisms are implicated in CFs activation and cardiac fibrosis, there is increasing evidence that epigenetic regulation plays a key role in this process. Epigenetics is a rapidly growing field in biology, and provides a modulated link between pathological stimuli and gene expression profiles, ultimately leading to corresponding pathological changes. Epigenetic modifications are mainly composed of three main categories: DNA methylation, histone modifications, and non-coding RNAs. This review focuses on recent advances regarding epigenetic regulation in cardiac fibrosis and highlights the effects of epigenetic modifications on CFs activation. Finally, we provide some perspectives and prospects for the study of epigenetic modifications and cardiac fibrosis.

Doxorubicin (DOX) is an effective anticancer drug, but its clinical utility is limited mainly by cardiotoxicity causing cardiomyocyte ferroptosis and apoptosis. While DOX-induced cardiotoxicity (DIC) involves epigenetic changes, no systematic epigenetic intervention studies have been reported. Here, we identified BRD4770 as a potential small molecule against DIC through the Epigenetics Compound Library screening. BRD4770 inhibited DOX-induced cardiomyocyte ferroptosis and apoptosis by reducing reactive oxygen species (ROS) production and lipid peroxidation and maintaining glutathione homeostasis. BRD4770 treatment alleviated DIC without affecting the antitumor effects of DOX. Mechanistically, BRD4770 promoted nuclear factor erythroid 2-related factor 2 (Nrf2)/activating transcription factor 4 (ATF4)–solute carrier family 7 member 11 (SLC7A11) signaling and suppressed DOX-induced cardiomyocyte death by reducing methylation of lysine 9 on histone 3. Last, we constructed a ROS-responsive nanoliposome loaded with BRD4770 and conjugated with the cardiac-targeting peptide for primary cardiomyocyte, which provided better protection against DIC. These findings suggest that BRD4770 has the potential to prevent cardiomyocyte death–related cardiomyopathy.

Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD). Renal sympathetic nerve activity is elevated in patients and experimental animals with CKD and contributes to renal interstitial fibrosis in obstructive nephropathy. However, the mechanisms underlying sympathetic overactivation in renal fibrosis remain unknown. Norepinephrine (NE), the main sympathetic neurotransmitter, was found to promote TGF‐β1‐induced epithelial‐mesenchymal transition (EMT) and fibrotic gene expression in the human renal proximal epithelial cell line HK‐2. Using both genetic and pharmacological approaches, we identified that NE binds Gαq‐coupled α1‐adrenoceptor (α1‐AR) to enhance EMT of HK‐2 cells by activating p38/Smad3 signaling. Inhibition of p38 diminished the NE‐exaggerated EMT process and increased the fibrotic gene expression in TGF‐β1‐treated HK‐2 cells. Moreover, the pharmacological blockade of α1‐AR reduced the kidney injury and renal fibrosis in a unilateral ureteral obstruction mouse model by suppressing EMT in the kidneys. Thus, sympathetic overactivation facilitates EMT of renal epithelial cells and fibrosis via the α1‐AR/p38/Smad3 signaling pathway, and α1‐AR inhibition may be a promising approach toward treating renal fibrosis.