Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.

Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicin-induced cardiotoxicity. Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50% decrease of mortality. These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.