The burden and management competency of cardiomyopathies in China: a nationwide survey study.

Background: The public health burden of cardiomyopathies and competency in their management by health agencies in China are not well understood. Methods: This study adopted a multi-stage sampling method for hospital selection. In the first stage, nationwide tertiary hospital recruitment was performed. As a result, 88 hospitals with the consent of the director of cardiology and access to an established electronic medical records system, were recruited. In the second stage, we sampled 66 hospitals within each geographic-economic stratification through a random sampling process. Data on (1) the outpatient and inpatient visits for cardiomyopathies between 2017 and 2021 and (2) the competency in the management of patients with cardiomyopathies, were collected. The competency of a hospital to provide cardiomyopathy care was evaluated using a specifically devised scale. Findings: The outpatient and inpatient visits for cardiomyopathies increased between 2017 and 2021 by 38.6% and 33.0%, respectively. Most hospitals had basic facilities for cardiomyopathy assessment. However, access to more complex procedures was limited, and the integrated management pathway needs improvement. Only 4 (6.1%) of the 66 participating hospitals met the criteria for being designated as a comprehensive cardiomyopathy center, and only 29 (43.9%) could be classified as a primary cardiomyopathy center. There were significant variations in competency between hospitals with different administrative and economic levels. Interpretation: The health burden of cardiomyopathies has increased significantly between 2017 and 2021 in China. Although most tertiary hospitals in China can offer basic cardiomyopathy care, more advanced facilities are not yet universally available. Moreover, inconsistencies in the management of cardiomyopathies across hospitals due to differing administrative and economic levels warrants a review of the nation allocation of medical resources. Funding: This work was supported by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2023-I2M-1-001) and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-17).

GAS41 modulates ferroptosis by anchoring NRF2 on chromatin.

YEATS domain-containing protein GAS41 is a histone reader and oncogene. Here, through genome-wide CRISPR-Cas9 screenings, we identify GAS41 as a repressor of ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter, independent of NRF2 binding. By bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes to its oncogenic role in vivo. These data demonstrate that GAS41 is a target for modulating tumor growth through ferroptosis. Our study reveals a mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin, and provides a model in which the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac).

Ferroptosis: Biology and Role in Gastrointestinal Disease.

Ferroptosis is a form of nonapoptotic cell death that involves iron-dependent phospholipid peroxidation induced by accumulation of reactive oxygen species, and results in plasma membrane damage and the release of damage-associated molecular patterns. Ferroptosis has been implicated in aging and immunity, as well as disease states including intestinal and liver conditions and cancer. To date, several ferroptosis-associated genes and pathways have been implicated in liver disease. Although ferroptotic cell death is associated with dysfunction of the intestinal epithelium, the underlying molecular basis is poorly understood. As the mechanisms regulating ferroptosis become further elucidated, there is clear potential to use ferroptosis to achieve therapeutic benefit.

Blockade of endothelial adenosine receptor 2A suppresses atherosclerosis in vivo through inhibiting CREB-ALK5-mediated endothelial to mesenchymal transition.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and morbidity and mortality rates continue to rise. Atherosclerosis constitutes the principal etiology of CVDs. Endothelial injury, inflammation, and dysfunction are the initiating factors of atherosclerosis. Recently, we reported that endothelial adenosine receptor 2A (ADORA2A), a G protein-coupled receptor (GPCR), plays critical roles in neovascularization disease and cerebrovascular disease. However, the precise role of endothelial ADORA2A in atherosclerosis is still not fully understood. Here, we showed that ADORA2A expression was markedly increased in the aortic endothelium of humans with atherosclerosis or Apoe-/- mice fed a high-cholesterol diet. In vivo studies unraveled that endothelial-specific Adora2a deficiency alleviated endothelial-to-mesenchymal transition (EndMT) and prevented the formation and instability of atherosclerotic plaque in Apoe-/- mice. Moreover, pharmacologic inhibition of ADORA2A with KW6002 recapitulated the anti-atherogenic phenotypes observed in genetically Adora2a-deficient mice. In cultured human aortic endothelial cells (HAECs), siRNA knockdown of ADORA2A or KW6002 inhibition of ADORA2A decreased EndMT, whereas adenoviral overexpression of ADORA2A induced EndMT. Mechanistically, ADORA2A upregulated ALK5 expression via a cAMP/PKA/CREB axis, leading to TGFß-Smad2/3 signaling activation, thereby promoting EndMT. In conclusion, these findings, for the first time, demonstrate that blockade of ADORA2A attenuated atherosclerosis via inhibition of EndMT induced by the CREB1-ALK5 axis. This study discloses a new link between endothelial ADORA2A and EndMT and indicates that inhibiting endothelial ADORA2A could be an effective novel strategy for the prevention and treatment of atherosclerotic CVDs.

PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.

Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.

Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.

Precisión diagnóstica de la TC-RFF con un nuevo algoritmo de subpíxel grueso a fino en la detección de isquemia específica de lesión: un estudio multicéntrico prospectivo / Diagnostic accuracy of CT-FFR with a new coarse-to-fine subpixel algorithm in detecting lesion-specific ischemia: a prospective multicenter study

Introduction and objectives A new computed tomography-derived fractional flow reserve (CT-FFR) technique with a “coarse-to-fine subpixel” algorithm has been developed to generate precise lumen contours. The aim of this study was to assess the diagnostic performance of this new CT-FFR algorithm for discriminating lesion-specific ischemia using wire-based FFR ≤ 0.80 as the reference standard in patients with coronary artery disease. Methods This prospective, multicenter study screened 330 patients undergoing coronary CT angiography (CCTA) and invasive FFR (median interval 2 days) from 6 tertiary hospitals. CT-FFR was evaluated in a blinded fashion with a “coarse-to-fine subpixel” algorithm for lumen contour. Results Between March 2019 and May 2020, we included 316 patients with 324 vessels. There was a good correlation between CT-FFR and invasive FFR (r=0.76, P<.001). The diagnostic sensitivity, specificity, and accuracy on a per-vessel level were 95.3%, 89.8%, and 92.0% for CT-FFR, and 96.4%, 26.4%, and 53.1% for CCTA>50% stenosis, respectively. CT-FFR showed improved discrimination of ischemia compared with CCTA alone overall (AUC, 0.95 vs 0.74, P<.001) and in intermediate (AUC, 0.96 vs 0.62, P<.001) and “gray zone” lesions (AUC, 0.88 vs 0.61, P<.001). The diagnostic specificity, accuracy, and AUC for CT-FFR (71.9%, 82.8%, and 0.84) outperformed CCTA (9.4%, 48.3%, and 0.66) in patients or in vessels with severe calcification (all P<.05). Conclusions CT-FFR with a new “coarse-to-fine subpixel” algorithm showed high performance in identifying hemodynamically significant stenosis. The diagnostic performance of CT-FFR was superior to that of CCTA in intermediate lesions, “gray zone” lesions, and severely calcified lesions (AU)

Introducción y objetivos Se ha desarrollado una nueva técnica basada en tomografía computarizada para la evaluación de la reserva fraccional de flujo (TC-RFF) con un algoritmo de subpíxel «de grueso a fino» para generar contornos luminales precisos. El objetivo de este estudio es evaluar el rendimiento diagnóstico de este nuevo algoritmo de TC-RFF para discriminar la isquemia específica de lesión utilizando la evaluación invasiva de la RFF ≤ 0,80 como referencia en pacientes con enfermedad coronaria. Métodos Este estudio prospectivo y multicéntrico evaluó a 330 pacientes sometidos a angiografía coronaria no invasiva con TC (ACTC) y evaluación invasiva de la RFF (mediana del intervalo, 2 días) en 6 hospitales terciarios. La TC-RFF se evaluó a ciegas con un algoritmo de subpíxel «de grueso a fino» para la evaluación de la luz. Resultado Entre marzo de 2019 y mayo de 2020, se incluyó a un total de 316 pacientes con 324 vasos. Hubo una buena correlación entre la TC-RFF y la evaluación invasiva de la RFF (r=0,76; p<0,001). La sensibilidad, la especificidad y la exactitud diagnóstica por vaso fueron, respectivamente, del 95,3, el 89,8 y el 92,0% para la TC-RFF y del 96,4, el 26,4 y el 53,1% para la ACTC para las estenosis>50%. La TC-RFF mostró mejor discriminación de la isquemia que la ACTC sola en general (ABC=0,95 frente a ABC=0,74; p<0,001) y en lesiones intermedias (ABC=0,96 frente a ABC=0,62; p<0,001) y en «zona gris» (ABC=0,88 frente a ABC=0,61; p<0,001). La especificidad, la exactitud y el ABC diagnóstica de la TC-RFF (el 71,9%, el 82,8% y 0,84) superaron las de la ACTC (el 9,4%, el 48,3% y 0,66) en pacientes o vasos con calcificación grave (todos, p<0,05). Conclusiones La TC-RFF con un algoritmo de subpíxel «de grueso a fino» proporcionó un alto rendimiento en la identificación de estenosis hemodinámicamente significativas. El rendimiento diagnóstico de la TC-RFF fue superior al de la ACTC en lesiones intermedias, de «zona gris» y con calcificación grave (AU)

A guideline on the molecular ecosystem regulating ferroptosis.

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

When CDK4/6i meets GPX4i: Stop dividing to die iron hard.

In this issue of Cell Chemical Biology, Rodencal et al.1 report that cell-cycle arrest by p53 stabilizers or CDK4/6 inhibitors (CDK4/6i) can lead to phospholipid remodeling and hence sensitize cancer cells to GPX4 inhibitor (GPX4i)-triggered ferroptosis. This study suggests a novel cancer therapeutic strategy combining CDK4/6i with GPX4i.

7-Dehydrocholesterol dictates ferroptosis sensitivity.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

Intramyocardial delivery of injectable hydrogel with arctigenin alleviated myocardial ischemia-reperfusion injury in rats.

Arctigenin belongs to a major bioactive component of Fructus arctii and has been found with cardioprotective effects on rats with ischemia-reperfusion (I/R) injury. The application of arctigenin is limited due to poor water solubility and low bioavailability. Hydrogel drug delivery systems can improve the efficacy and safety of drugs, increase drug utilization, and reduce side effects. We hypothesized that hydrogels containing arctigenin would facilitate the effect of arctigenin and alleviate I/R injury in the rat heart. Presently, adult Sprague-Dawley (SD) rats were subjected to 1 h of I/R injury, then hydrogels comprising arctigenin were implanted into the myocardium of rats. Triphenyl tetrazolium chloride staining, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and Western blot were performed for evaluating the infarct size, histopathological, and vital protein alterations of hearts. It was discovered that the hydrogel combined with arctigenin abated apoptosis and reduced infarct size. In addition, the results of echocardiography and Masson staining suggested that the hydrogel with arctigenin improved cardiac function, restrained myocardial fibrosis, and activated AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). Collectively, the injectable hydrogel delivery system enhances the effect of arctigenin, which may play a protective role in I/R injury by activating AMPK and SIRT1.

Diagnostic accuracy of CT-FFR with a new coarse-to-fine subpixel algorithm in detecting lesion-specific ischemia: a prospective multicenter study.

INTRODUCTION AND OBJECTIVES: A new computed tomography-derived fractional flow reserve (CT-FFR) technique with a "coarse-to-fine subpixel" algorithm has been developed to generate precise lumen contours. The aim of this study was to assess the diagnostic performance of this new CT-FFR algorithm for discriminating lesion-specific ischemia using wire-based FFR ≤ 0.80 as the reference standard in patients with coronary artery disease. METHODS: This prospective, multicenter study screened 330 patients undergoing coronary CT angiography (CCTA) and invasive FFR (median interval 2 days) from 6 tertiary hospitals. CT-FFR was evaluated in a blinded fashion with a "coarse-to-fine subpixel" algorithm for lumen contour. RESULTS: Between March 2019 and May 2020, we included 316 patients with 324 vessels. There was a good correlation between CT-FFR and invasive FFR (r=0.76, P<.001). The diagnostic sensitivity, specificity, and accuracy on a per-vessel level were 95.3%, 89.8%, and 92.0% for CT-FFR, and 96.4%, 26.4%, and 53.1% for CCTA>50% stenosis, respectively. CT-FFR showed improved discrimination of ischemia compared with CCTA alone overall (AUC, 0.95 vs 0.74, P<.001) and in intermediate (AUC, 0.96 vs 0.62, P<.001) and "gray zone" lesions (AUC, 0.88 vs 0.61, P<.001). The diagnostic specificity, accuracy, and AUC for CT-FFR (71.9%, 82.8%, and 0.84) outperformed CCTA (9.4%, 48.3%, and 0.66) in patients or in vessels with severe calcification (all P<.05). CONCLUSIONS: CT-FFR with a new "coarse-to-fine subpixel" algorithm showed high performance in identifying hemodynamically significant stenosis. The diagnostic performance of CT-FFR was superior to that of CCTA in intermediate lesions, "gray zone" lesions, and severely calcified lesions. Clinical Trial Register: NCT04731285.

COVID-19 in Systemic Lupus Erythematosus patients treated with belimumab: a retrospective clinical study.

BACKGROUND: Routine use of immunosuppressive agents in systemic lupus erythematosus (SLE) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potentially increases the risk of adverse outcomes. belimumab, a monoclonal antibody for the treatment of SLE, remains untested for its specific impact on coronavirus disease 2019 (COVID-19) symptoms in these patients. Here, this research investigated the effect of belimumab on COVID-19 symptoms in SLE patients infected with SARS-CoV-2. METHODS: This study enrolled SLE patients who underwent treatment with belimumab. After thorough screening based on the inclusion and exclusion criteria, data pertaining to COVID-19 for both the participants and their cohabitants were obtained through telephone follow-up. The potential impact of belimumab on COVID-19 was evaluated by comparing COVID-19 symptoms and medication use across various groups to investigate the association between belimumab treatment and COVID-19 in SLE. RESULTS: This study involved 123 SLE patients, of whom 89.4% tested positive for SARS-CoV-2. Among cohabitants of SLE patients, the SARS-CoV-2 positive rate was 87.2% (p = 0.543). Patients treated with belimumab exhibited a lower incidence of multiple COVID-19 symptoms than their cohabitating counterparts (p < 0.001). This protective effect was found to be partially related to the time of last belimumab administration. Among those with COVID-19, 30 patients opted to discontinue their anti-SLE drugs, and among them, 53% chose to discontinue belimumab. Discontinuing drugs did not increase the risk of hospitalization due to SARS-CoV-2 infection. CONCLUSION: This study concluded that treatment with belimumab did not increase susceptibility to COVID-19 and beneficially alleviated the symptoms of COVID-19.

Comparison between a dedicated stent positioning system and conventional stenting of aorto-ostial lesions: a prospective, multi-center, randomized controlled study.

Background: The accurate placement of stents for treatment of coronary aorto-ostial lesions (AOLs) is technically challenging. The purpose of this study was to evaluate the efficacy and safety of a stent positioning system with a dedicated nitinol device and compare them with those of the conventional approach for stenting of coronary AOLs. Methods: In this prospective, multi-center, open-label, randomized study, conducted from November 2015 to April 2019, patients with coronary AOLs that underwent percutaneous coronary intervention (PCI) were randomly allocated (allocation ratio 1:1) using block randomization method to either a stent positioning system group or a conventional technique group. The primary endpoint was the range of stent slippage when positioning. The following secondary endpoints were applied: (I) the extent of swing of the guiding catheters during stent positioning; (II) the rate of accurate stent placement; (III) the procedure time; and (IV) the incidence of major adverse cardiovascular events (MACEs) including cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis. Results: During the study period, 139 patients with aorto-ostial coronary artery stenosis were included at 5 centers. A total of 69 patients were allocated to the stent positioning system group and 70 patients to the conventional technique group. Angiographic and clinical success were achieved in 100% of the patients included in both groups. The range of stent slippage was significantly shorter in the stent positioning system group than it was in the conventional technique group [0.64 (0.22; 1.35) vs. 1.11 (0.48; 1.72) mm, P=0.01]. The rate of accurate placement of stents was higher in the stent positioning system group than it was in the conventional technique group (74.6% vs. 57.1%, P=0.03). The extent of guiding catheter swing during the stent positioning [0.24 (0.19; 0.53) vs. 0.23 (0.19; 0.53) mm; P=0.95] and the MACEs rates (1.4% vs. 2.9%, P>0.99) were similar between the 2 groups. The procedural time of the stent positioning system was longer than that of the conventional approach [1.00 (0.50; 1.50) vs. 0.80 (0.50; 1.50) min, P=0.09]. Conclusions: The dedicated stent positioning system was is safer and provides more accurate placement of stents for coronary AOLs than the conventional approach, and the associated prolongation of procedure time is insignificant. Trial Registration: Chinese Clinical Trial Registry (ChiCTR), Unique identifier: ChiCTR2100053869. URL: https://www.chictr.org.cn/showproj.html?proj=133280.

Germacrone mitigates cardiac remodeling by regulating PI3K/AKT-mediated oxidative stress, inflammation, and apoptosis.

Cardiac remodeling is a common consequence of cardiovascular diseases and is closely associated with oxidative stress, inflammation, and apoptosis. Germacrone, a bioactive compound present in Rhizoma curcuma, has been shown to possess anti-oxidative, anti-inflammatory, and anti-apoptotic properties. The aim of this study was to investigate the protective effect of germacrone against cardiac remodeling. Here, C57BL/6 mice were subcutaneous injection with isoproterenol (ISO) once daily for two weeks and were concurrent intragastric injection of germacrone. In vitro, neonatal rat cardiomyocytes (NRCMs) were used to verify the protective effect of germacrone on ISO-induced cardiac injury. Our findings indicated that ISO induce oxidative stress, inflammation, and apoptosis in vivo and in vitro, while germacrone treatment significantly attenuates these effects, thereby attenuating myocardium remodeling and cardiac dysfunction. Mechanistically, germacrone reduced cardiac remodeling-induced activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, and the cardioprotective effects of germacrone were abrogated by a PI3K agonist. In conclusion, our results suggest that germacrone attenuates oxidative stress, inflammation, and apoptosis in cardiac remodeling by inhibiting the PI3K/AKT pathway, and may therefore represent a promising therapeutic approach for the treatment of cardiac remodeling.

Curcumol alleviates cardiac remodeling via the AKT/NF-κB pathway.

Cardiac remodeling is the final stage of almost all cardiovascular diseases, leading to heart failure and arrhythmias. However, the pathogenesis of cardiac remodeling is not fully understood, and specific treatment schemes are currently unavailable. Curcumol is a bioactive sesquiterpenoid that has anti-inflammatory, anti-apoptotic, and anti-fibrotic properties. This study aimed to investigate the protective effect of curcumol on cardiac remodeling and elucidate its relevant underlying mechanism. Curcumol significantly attenuated cardiac dysfunction, myocardial fibrosis, and hypertrophy in the animal model of isoproterenol (ISO)-induced cardiac remodeling. Curcumol also alleviated cardiac electrical remodeling, thereby reducing the risk of ventricular fibrillation (VF) after heart failure. Inflammation and apoptosis are critical pathological processes involved in cardiac remodeling. Curcumol inhibited the inflammation and apoptosis induced by ISO and TGF-ß1 in mouse myocardium and neonatal rat cardiomyocytes (NRCMs). Furthermore, the protective effects of curcumol were found to be mediated through the inhibition of the protein kinase B (AKT)/nuclear factor-kappa B (NF-κB) pathway. The administration of an AKT agonist reversed the anti-fibrotic, anti-inflammatory, and anti-apoptotic effects of curcumol and restored the inhibition of NF-κB nuclear translocation in TGF-ß1-induced NRCMs. Our study suggests that curcumol is a potential therapeutic agent for the treatment of cardiac remodeling.

Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism.

Here, we identified vitamin K epoxide reductase complex subunit 1 like 1 (VKORC1L1) as a potent ferroptosis repressor. VKORC1L1 protects cells from ferroptosis by generating the reduced form of vitamin K, a potent radical-trapping antioxidant, to counteract phospholipid peroxides independent of the canonical GSH/GPX4 mechanism. Notably, we found that VKORC1L1 is also a direct transcriptional target of p53. Activation of p53 induces downregulation of VKORC1L1 expression, thus sensitizing cells to ferroptosis for tumor suppression. Interestingly, a small molecular inhibitor of VKORC1L1, warfarin, is widely prescribed as an FDA-approved anticoagulant drug. Moreover, warfarin represses tumor growth by promoting ferroptosis in both immunodeficient and immunocompetent mouse models. Thus, by downregulating VKORC1L1, p53 executes the tumor suppression function by activating an important ferroptosis pathway involved in vitamin K metabolism. Our study also reveals that warfarin is a potential repurposing drug in cancer therapy, particularly for tumors with high levels of VKORC1L1 expression.

Phloretin ameliorates heart function after myocardial infarction via NLRP3/Caspase-1/IL-1ß signaling.

OBJECTIVES/AIMS: Inflammation is crucial in structural and electrical remodeling after myocardial infarction (MI), affecting cardiac pump function and conduction pathways. Phloretin possesses an anti-inflammation role by inhibiting the NLRP3/Caspase-1/IL-1ß pathway. However, the effects of Phloretin on cardiac contractile and electrical conduction function after MI remained unclear. Therefore, we aimed to investigate the potential role of Phloretin in a rat model of MI. METHODS: Rats were assigned into four groups: Sham, Sham+Phloretin, MI and MI+Phloretin, with ad libitum food and water. In the MI and MI+Phloretin groups, the left anterior descending coronary artery was occluded for 4 weeks, while the Sham and Sham+Phloretin groups received sham operation. The Sham+Phloretin group and the MI+Phloretin group received oral administration of Phloretin. In vitro, H9c2 cells were subjected to hypoxic conditions to simulate an MI model, with Phloretin for 24 h. Cardiac electrophysiological properties were assessed following MI, including the effective refractory period (ERP), action potential duration (APD)90 and ventricular fibrillation (VF) incidence. Echocardiography evaluated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) to assess cardiac function. Serum type B natriuretic peptide (BNP) level was applied to evaluate the degree of Heart failure (HF). The fibrosis area and severity were assessed by Masson staining and protein expression levels of collagen 3, collagen 1, TGF-ß and α-SMA. Western blot analysis estimated the protein expression levels of NLRP3, Pro Caspase-1, Caspase-1, ASC, IL-18, IL-1ß, pp38, p38, and Connexin43(Cx43) to elucidate the influence of inflammation on electrical remodeling after MI. RESULTS: Our findings demonstrate that Phloretin inhibits the NLRP3/Caspase-1/IL-1ß pathway, leading to the upregulation of Cx43 by limiting p38 phosphorylation, which further decreases susceptibility to ventricular arrhythmias (VAs). Additionally, Phloretin attenuated fibrosis by inhibiting inflammation to prevent HF. In vitro experiments also provided strong evidence supporting the inhibitory effects of Phloretin on the NLRP3/Caspase-1/IL-1ß pathway. CONCLUSION: Our results suggest that Phloretin could suppress the NLRP3/Caspase-1/IL-1ß pathway to reverse structural and electrical remodeling after MI to prevent the occurrence of VAs and HF.

Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.

Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.