Regulation of NCOA4-mediated iron recycling ameliorates paraquat-induced lung injury by inhibiting ferroptosis.

Paraquat (PQ) is an irreplaceable insecticide in many countries for the advantage of fast-acting and broad-spectrum. However, PQ was classified as the most prevailing poisoning substance for suicide with no specific antidote. Therefore, it is imperative to develop more effective therapeutic agents for the treatment of PQ poisoning. In the present study, both the RNA-Seq and the application of various cell death inhibitors reflected that ferroptosis exerts a crucial regulatory role in PQ poisoning. Moreover, we found PQ strengthens lipid peroxidation as evidenced by different experimental approaches. Of note, pretreatment of iron chelation agent DFO could ameliorate the ferroptotic cell death and alleviate the ferroptosis-related events. Mechanistically, PQ treatment intensively impaired mitochondrial homeostasis, enhanced phosphorylation of AMPK, accelerated the autophagy flux and triggered the activation of Nuclear receptor coactivator 4-ferritin heavy chain (NCOA4-FTH) axis. Importantly, the activation of autophagy was observed prior to the degradation of ferritin, and inhibition of autophagy could inhibit the accumulation of iron caused by the ferritinophagy process. Genetic and pharmacological inhibition of ferritinophagy could alleviate the lethal oxidative events, and rescue the ferroptotic cell death. Excitingly, in the mouse models of PQ poisoning, both the administration of DFO and adeno-associated virus-mediated FTH overexpression significantly reduced PQ-induced ferroptosis and improved the pathological characteristics of pulmonary fibrosis. In summary, the current work provides an in-depth study on the mechanism of PQ intoxication, describes a framework for the further understanding of ferroptosis in PQ-associated biological processes, and demonstrates modulation of iron metabolism may act as a promising therapeutic agent for the management of PQ toxicity.

Immunotherapies of acute myeloid leukemia: Rationale, clinical evidence and perspective.

Acute myeloid leukemia (AML) is a prevalent hematological malignancy that exhibits a wide array of molecular abnormalities. Although traditional treatment modalities such as chemotherapy and allogeneic stem cell transplantation (HSCT) have become standard therapeutic approaches, a considerable number of patients continue to face relapse and encounter a bleak prognosis. The emergence of immune escape, immunosuppression, minimal residual disease (MRD), and other contributing factors collectively contribute to this challenge. Recent research has increasingly highlighted the notable distinctions between AML tumor microenvironments and those of healthy individuals. In order to investigate the potential therapeutic mechanisms, this study examines the intricate transformations occurring between leukemic cells and their surrounding cells within the tumor microenvironment (TME) of AML. This review classifies immunotherapies into four distinct categories: cancer vaccines, immune checkpoint inhibitors (ICIs), antibody-based immunotherapies, and adoptive T-cell therapies. The results of numerous clinical trials strongly indicate that the identification of optimal combinations of novel agents, either in conjunction with each other or with chemotherapy, represents a crucial advancement in this field. In this review, we aim to explore the current and emerging immunotherapeutic methodologies applicable to AML patients, identify promising targets, and emphasize the crucial requirement to augment patient outcomes. The application of these strategies presents substantial therapeutic prospects within the realm of precision medicine for AML, encompassing the potential to ameliorate patient outcomes.

The dual function of cGAS-STING signaling axis in liver diseases.

Numerous liver diseases, such as nonalcoholic fatty liver disease, hepatitis, hepatocellular carcinoma, and hepatic ischemia-reperfusion injury, have been increasingly prevalent, posing significant threats to global health. In recent decades, there has been increasing evidence linking the dysregulation of cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING)-related immune signaling to liver disorders. Both hyperactivation and deletion of STING can disrupt the immune microenvironment dysfunction, exacerbating liver disorders. Consequently, there has been a surge in research investigating medical agents or mediators targeting cGAS-STING signaling. Interestingly, therapeutic manipulation of the cGAS-STING pathway has yielded inconsistent and even contradictory effects on different liver diseases due to the distinct physiological characteristics of intrahepatic cells that express and respond to STING. In this review, we comprehensively summarize recent advancements in understanding the dual roles of the STING pathway, highlighting that the benefits of targeting STING signaling depend on the specific types of target cells and stages of liver injury. Additionally, we offer a novel perspective on the suitability of STING agonists and antagonists for clinical assessment. In conclusion, STING signaling remains a highly promising therapeutic target, and the development of STING pathway modulators holds great potential for the treatment of liver diseases.

Acteoside ameliorates hepatic ischemia-reperfusion injury via reversing the senescent fate of liver sinusoidal endothelial cells and restoring compromised sinusoidal networks.

Hepatic ischemia-reperfusion injury (HIRI), a common two-phase intersocietal reaction in liver surgery, typically leading to sustained liver dysfunction. During this process, liver sinusoidal endothelial cells (LSECs) are vulnerable to damage and exert senescence-associated secretory phenotype (SASP). However, how these SASP-LSECs secreted damage-associated molecular patterns (DAMPs) to impact the whole HIRI microenvironment and whether it can be reversed by therapeutics remains unknown. Here, we found that either HIRI surgery or hypoxia and reoxygenation (HR) stimulation forced LSECs into SASP and expressed HMGB1-dominated DAMPs, which were dramatically improved by acteoside (ACT). Additionally, hypoxic hepatocytes released excessive HMGB1 to LSECs and synergistically aggravated their SASP state. Mechanistically, HMGB1 bound with TLR3/TLR4 on LSECs, promoted the nuclear translocation of IRF1 and subsequent transcription of cxcl1 and Hmgb1, leading to the chemotaxis of neutrophils and accelerating immune damage in a vicious circle. Notably, ACT or HMGB1 siRNA effectively disrupted HMGB1-TLR3/4 interaction, leading to IRF1 inhibition and repairing LSEC functions, which was largely reversed by HMGB1 stimulation and IRF1-overexpressed liposomes with LSECs-targeted hyaluronic acid-derivative conjugated in mice. Collectively, ACT reversed the senescent fate of LSECs and restored sinusoidal networks by targeting HMGB1-TLR3/4-IRF1 signaling, thus providing protection against HIRI and offering the potential for new therapeutics development.

A novel pulmonary fibrosis murine model with immune-related liver injury.

Idiopathic pulmonary fibrosis (IPF), characterized by aggravated alveolar destruction and fibrotic matrix deposition, tendentiously experiences the stage called acute exacerbation IPF (AE-IPF) and progresses to multiple organ damage, especially liver injury. Recent studies have found a variety of immune microenvironment disorders associated with elevated IPF risk and secondary organ injury, whereas current animal models induced with bleomycin (BLM) could not completely reflect the pathological manifestations of AE-IPF patients in clinic, and the exact underlying mechanisms are not yet fully explored. In the current study, we established an AE-IPF model by tracheal administration of a single dose of BLM and then repeated administrations of lipopolysaccharide in mice. This mouse model successfully recapitulated the clinical features of AE-IPF, including excessive intrapulmonary inflammation and fibrosis and extrapulmonary manifestations, as indicated by significant upregulation of Il6, Tnfa, Il1b, Tgfb, fibronectin, and Col1a1 in both lungs and liver and elevated serum aspartate transaminase and alanine transaminase levels. These effects might be attributed to the regulation of Th17 cells. By sharing this novel murine model, we expect to provide an appropriate experimental platform to investigate the pathogenesis of AE-IPF coupled with liver injury and contribute to the discovery and development of targeted interventions.

Characterization of pyruvate metabolism and citric acid cycle patterns predicts response to immunotherapeutic and ferroptosis in gastric cancer.

BACKGROUND: Gastric cancer is one of the most common malignancies of the digestive system with a high lethal rate. Studies have shown that inherited and acquired mutations in pyruvate metabolism and citric acid cycle (P-CA) enzymes are involved in tumorigenesis and tumor development. However, it is unclear how different P-CA patterns affect the tumor microenvironment (TME), which is critical for cancer progression. METHODS: This study mainly concentrated on investigating the role of the P-CA patterns in multicellular immune cell infiltration of GC TME. First, the expression levels of P-CA regulators were profiled in GC samples from The Cancer Genome Atlas and Gene Expression Omnibus cohorts to construct a consensus clustering analysis and identify three distinct P-CA clusters. GSVA was conducted to reveal the different biological processes in three P-CA clusters. Subsequently, 1127 cluster-related differentially expressed genes were identified, and prognostic-related genes were screened using univariate Cox regression analysis. A scoring system was then set up to quantify the P-CA gene signature and further evaluate the response of the patients to the immunotherapy. RESULTS: We found that GC patients in the high P-CA score group had a higher tumor mutational burden, higher microsatellite instability, and better prognosis. The opposite was observed in the low P-CA score group. Interestingly, we demonstrated P-CA gene cluster could predict the sensitivity to immunotherapy and ferroptosis-induced therapy. CONCLUSION: Collectively, the P-CA gene signature in this study exhibits potential roles in the tumor microenvironment and predicts the response to immunotherapeutic. The identification of these P-CA patterns may significantly accelerate the strategic development of immunotherapy for GC.

Extracellular vesicles: catching the light of intercellular communication in fibrotic liver diseases.

The increasing prevalence of fibrotic liver diseases resulting from different etiologies has become a major global problem for public health. Fibrotic liver diseases represent a redundant accumulation of extracellular matrix, dysregulation of immune homeostasis and angiogenesis, which eventually contribute to the progression of cirrhosis and liver malignancies. The concerted actions among liver cells including hepatocytes, hepatic stellate cells, kupffer cells, liver sinusoidal endothelial cells and other immune cells are essential for the outcome of liver fibrosis. Recently, a growing body of literature has highlighted that extracellular vesicles (EVs) are critical mediators of intercellular communication among different liver cells either in local or distant microenvironments, coordinating a variety of systemic pathological and physiological processes. Despite the increasing interests in this field, there are still relatively few studies to classify the contents and functions of EVs in intercellular transmission during hepatic fibrogenesis. This review aims to summarize the latest findings with regards to the cargo loading, release, and uptake of EVs in different liver cells and clarify the significant roles of EVs played in fibrotic liver diseases.