Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension.

Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. Recent advances suggest that macrophages coordinate interactions among different proinflammatory and anti-inflammatory mediators, and other cellular components such as smooth muscle cells and fibroblasts. In this review, we summarize the current literature on the role of macrophages in the pathogenesis of pulmonary hypertension, including the origin of pulmonary macrophages and their response to triggers of pulmonary hypertension. We then discuss the interactions among macrophages, cytokines, and vascular adventitial fibroblasts in pulmonary hypertension, as well as the potential therapeutic benefits of macrophages in this disease. Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

FTH1 overexpression using a dCasRx translation enhancement system protects the kidney from calcium oxalate crystal-induced injury.

The engineered clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) system is currently widely applied in genetic editing and transcriptional regulation. The catalytically inactivated CasRx (dCasRx) has the ability to selectively focus on the mRNA coding region without disrupting transcription and translation, opening up new avenues for research on RNA modification and protein translation control. This research utilized dCasRx to create a translation-enhancement system for mammals called dCasRx-eIF4GI, which combined eukaryotic translation initiation factor 4G (eIF4GI) to boost translation levels of the target gene by recruiting ribosomes, without affecting mRNA levels, ultimately increasing translation levels of different endogenous proteins. Due to the small size of dCasRx, the dCasRx-eIF4GI translation enhancement system was integrated into a single viral vector, thus optimizing the delivery and transfection efficiency in subsequent applications. Previous studies reported that ferroptosis, mediated by calcium oxalate (CaOx) crystals, significantly promotes stone formation. In order to further validate its developmental potential, it was applied to a kidney stone model in vitro and in vivo. The manipulation of the ferroptosis regulatory gene FTH1 through single-guide RNA (sgRNA) resulted in a notable increase in FTH1 protein levels without affecting its mRNA levels. This ultimately prevented intracellular ferroptosis and protected against cell damage and renal impairment caused by CaOx crystals. Taken together, this study preliminarily validated the effectiveness and application prospects of the dCasRx-eIF4GI translation enhancement system in mammalian cell-based disease models, providing novel insights and a universal tool platform for protein translation research and future therapeutic approaches for nephrolithiasis.

The role and therapeutic potential of itaconate in lung disease.

Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential.

Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis.

Acute pancreatitis (AP) is an acute inflammatory disorder characterized by acinar cell death and inflammation. Multiple factors cause hyperglycemia after AP. Macrophage polarization is involved in tissue injury and repair, and is regulated by Notch signaling during certain inflammatory diseases. The present study explores the relationship among hyperglycemia, macrophage polarization, and Notch signaling during AP and the related mechanisms. A cerulein-induced AP model was established in FVB/N mice, and AP with hyperglycemia was initiated by injection of 50% concentration glucose. Tissue damage, Notch activity, and macrophage polarization were assessed in pancreatic tissues. The role of Notch signaling in macrophage polarization during AP was also assessed in vitro by co-culturing primary macrophages and pancreatic acinar cells, and establishing a lipopolysaccharide (LPS)-induced inflammatory model in RAW264.7 cells. Pancreatic acinar cells were damaged and proinflammatory factor levels were increased in pancreatic tissues during AP. The hyperglycemic conditions aggravated pancreatic injury, increased macrophage infiltration, promoted macrophage polarization towards an M1 phenotype, and led to excessive up-regulation of Notch activity. Inhibition of Notch signaling by DAPT or Notch1 knockdown decreased the proportion of M1 macrophages and reduced the production of proinflammatory factors, thus mitigating pancreatic injury. These findings suggest that hyperglycemia induces excessive Notch signaling after AP and further aggravates AP by promoting pancreatic macrophage polarization towards the M1 phenotype. The Notch signaling pathway is a potential target for the prevention and treatment of AP.

Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway.

BACKGROUND: NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated macrophage pyroptosis plays an important role in sepsis-induced acute lung injury (ALI). Inhibition of pyroptosis may be a way to alleviate inflammation as well as tissue damage triggered after lipopolysaccharide (LPS) stimulation. The aim of the present study was to explore whether buformin (BF), a hypoglycemic agent, could alleviate sepsis-induced ALI by inhibiting pyroptosis. METHODS: Wildtype C57BL/6 mice were randomly divided into control group, BF group, LPS group and LPS+BF group. BF group and LPS+BF group were pretreated with BF at a dose of 25 mg/kg, and the changes were observed. In addition, BF was used to interfere with THP-1 cells. The therapeutic effect of BF has been verified by intraperitoneal injection of BF in vivo after LPS stimulation. RESULTS: Inflammation and injury was significantly reduced in BF pretreated mice, and the indexes related to pyroptosis were suppressed. The phosphorylation of AMP-activated protein kinase (AMPK) in lung tissues of mice in the BF and LPS+BF groups was significantly higher. In THP-1 cells, the AMPK inhibitor, Compound C was added to demonstrate that BF worked via AMPK to inhibit NLRP3 inflammasome. It was further demonstrated that BF up-regulated autophagy, which in turn promoted NLRP3 inflammasome degradation. On the other hand, BF decreased NLRP3 mRNA level by increasing nuclear factor-erythroid 2 related factor 2 (Nrf2). And BF showed a therapeutic effect after LPS challenge. CONCLUSION: Our study confirmed that BF inhibited NLRP3-mediated pyroptosis in sepsis-induced ALI by up-regulating autophagy and Nrf2 protein level through an AMPK-dependent pathway. This provides a new strategy for clinical mitigation of sepsis-induced ALI.

PM2.5-induced lung injury is attenuated in macrophage-specific NLRP3 deficient mice.

Fine particulate matter (PM2.5) is one of the most important components of environmental pollutants and is associated with lung injury. Pyroptosis, a form of programmed cell death mainly mediated by the NLRP3 inflammasome, has been reported to be involved in sepsis-induced or ischemia/reperfusion-induced lung injury. However, the specific mechanisms of pyroptosis in PM2.5-induced lung injury are not yet clear. We constructed macrophage-specific NLRP3 knockout mice to explore the mechanism of PM2.5-induced lung injury in terms of inflammatory response, oxidative stress, and apoptosis levels, including the relationship between these effects and pyroptosis. The results disclosed that PM2.5 exposure increased the infiltration of macrophages and leukocytes and the secretion of inflammatory cytokines, including TNF-α and IL-6, in lung tissue. The activity of antioxidant enzymes, including SOD, GSH-PX, and CAT, significantly decreased, while MDA, the end product of lipid oxidation, remarkably increased. The level of apoptosis in lung tissue, measured by the TUNEL assay and apoptosis-related proteins (BAX and BCL-2), was significantly increased. Macrophage-specific NLRP3 knockout could offset these effects. We further observed that PM2.5 treatment activated the NLRP3 inflammasome and subsequently induced pyroptosis, as evidenced by the increased production of IL-1ß and IL-18 and the increase of the protein levels of NLRP3, ASC, caspase-1, and GSDMD, which were inhibited when NLRP3 was knocked out in macrophages. Taken together, these results revealed that NLRP3-mediated macrophage pyroptosis promoted PM2.5-induced lung injury through aggravating inflammation, oxidative stress, and apoptosis. Targeting the inhibition of NLRP3-mediated macrophage pyroptosis provides a new way to study lung injury induced by the exposure to PM2.5.

Primary squamous cell carcinoma and adenocarcinoma simultaneously occurring in the same lung lobe: a case report and literature review.

The co-occurrence of distinct lung cancer types within the same lobe is an exceedingly rare phenomenon. Here, we present a unique case wherein primary invasive squamous cell carcinoma and invasive adenocarcinoma concurrently manifested in the identical lung lobe. Additionally, we provide a comprehensive overview of the diagnosis and treatment approaches for multiple primary lung cancers, along with highlighting existing challenges based on the most recent guidelines. Our case underscores the importance of sampling each lesion individually, conducting separate diagnostic procedures, and determining the histological subtype for effective treatment planning irrespective of their location or size.

HDAC3 in action: Expanding roles in inflammation and inflammatory diseases.

Inflammation serves as the foundation for numerous physiological and pathological processes, driving the onset and progression of various diseases. Histone deacetylase 3 (HDAC3), an essential chromatin-modifying protein within the histone deacetylase superfamily, exerts its transcriptional inhibitory role through enzymatic histone modification to uphold normal physiological function, growth, and development of the body. With both enzymatic and non-enzymatic activities, HDAC3 plays a pivotal role in regulating diverse transcription factors associated with inflammatory responses and related diseases. This review examines the involvement of HDAC3 in inflammatory responses while exploring its therapeutic potential as a target for treating inflammatory diseases, thereby offering valuable insights for clinical applications.

The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases.

HDAC3 is a specific and crucial member of the HDAC family. It is required for embryonic growth, development, and physiological function. The regulation of oxidative stress is an important factor in intracellular homeostasis and signal transduction. Currently, HDAC3 has been found to regulate several oxidative stress-related processes and molecules dependent on its deacetylase and non-enzymatic activities. In this review, we comprehensively summarize the knowledge of the relationship of HDAC3 with mitochondria function and metabolism, ROS-produced enzymes, antioxidant enzymes, and oxidative stress-associated transcription factors. We also discuss the role of HDAC3 and its inhibitors in some chronic cardiovascular, kidney, and neurodegenerative diseases. Due to the simultaneous existence of enzyme activity and non-enzyme activity, HDAC3 and the development of its selective inhibitors still need further exploration in the future.

Oral Hydroxychloroquine Mitigates Lipopolysaccharide-induced Lung Injury by Inhibiting Pyroptosis in Mice.

BACKGROUND AND OBJECTIVE: Hydroxychloroquine (HCQ) is a molecule derived from quinacrine; it displays a wide range of pharmacological properties, including anti-inflammatory, immunomodulatory, and antineoplastic. However, little is known about this molecule's role in lung injury. This study aimed to identify HCQ's regulatory role of HCQ in sepsis-induced lung injury and its molecular mechanism. METHODS: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis. RESULTS: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1ß, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice. CONCLUSION: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.

TMEM16A deficiency in alveolar type 2 epithelial cells protected against endoplasmic reticulum stress-induced ferroptosis during acute lung injury.

Transmembrane protein 16A (TMEM16A) is one of the members of the ten-member family of "transmembrane protein 16", playing critical roles in infection and solid organ injury. Acute lung injury (ALI) is a devastating disease which could be triggered by sepsis, trauma, and ischemia reperfusion. However, molecular mechanisms contributing to ALI are poorly understood at presently. In this study, we investigated the role of TMEM16A in sepsis-induced ALI using TMEM16A-deficient mice. Sepsis-induced ALI model was established by intratracheal injection of lipopolysaccharide (LPS). Our results showed that LPS stimulation significantly upregulated the expression levels of TMEM16A in lung tissues and in alveolar epithelial type II (AT2) cells. Knockout of TMEM16A in AT2 cells significantly improved pulmonary function and alleviated lung pathological injury in LPS-treated mice. Meanwhile, TMEM16A deficiency also inhibited endoplasmic reticulum (ER) stress and ferroptosis in AT2 cells from LPS-treated mice. In vitro experiments further demonstrated that ER stress and ferroptosis were inhibited after TMEM16A was knocked out. Furthermore, we used ER stress inducer thapsigargin to induce ER stress in TMEM16A-null AT2 cells and found that the induction of ER stress abolished the inhibition of ferroptosis by TMEM16A deficiency in LPS-treated AT2 cells. Finally, we disclosed that pharmacological inhibition of TMEM16A by shikonin also showed similar therapeutic effect on LPS-induced ALI in vivo. In conclusion, TMEM16A deficiency in AT2 cells could alleviate sepsis-induced ALI by decreasing ER stress-induced ferroptosis during ALI.

HDAC3 promotes macrophage pyroptosis via regulating histone deacetylation in acute lung injury.

Activated inflammation and pyroptosis in macrophage are closely associated with acute lung injury (ALI). Histone deacetylase 3 (HDAC3) serves as an important enzyme that could repress gene expression by mediating chromatin remodeling. In this study, we found that HDAC3 was highly expressed in lung tissues of lipopolysaccharide (LPS)-treated mice. Lung tissues from macrophage HDAC3-deficient mice stimulated with LPS showed alleviative lung pathological injury and inflammatory response. HDAC3 silencing significantly blocked the activation of cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in LPS-induced macrophage. LPS could recruit HDAC3 and H3K9Ac to the miR-4767 gene promoter, which repressed the expression of miR-4767 to promote the expression of cGAS. Taken together, our findings demonstrated that HDAC3 played a pivotal role in mediating pyroptosis in macrophage and ALI by activating cGAS/STING pathway through its histone deacetylation function. Targeting HDAC3 in macrophage may provide a new therapeutic target for the prevention of LPS-induced ALI.

Pretreatment with Kahweol Attenuates Sepsis-Induced Acute Lung Injury via Improving Mitochondrial Homeostasis in a CaMKKII/AMPK-Dependent Pathway.

SCOPE: It is well-established that dysregulated mitochondrial homeostasis in macrophages leads to inflammation, oxidative stress, and tissue damage, which are essential in the pathogenesis of sepsis-induced acute lung injury (ALI). Kahweol, a natural diterpene extracted from coffee beans, reportedly possesses anti-inflammatory and mitochondrial protective properties. Herein, the study investigates whether Kahweol can alleviate sepsis-induced ALI and explore the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are intraperitoneally injected with lipopolysaccharide (LPS) for 12 h to induce ALI. Pretreatment with kahweol by gavage for 5 days significantly alleviates lung pathological injury, inflammation, and oxidative stress, accompanied by shifting the dynamic process of mitochondria from fission to fusion, enhancing mitophagy, and activating AMPK. To investigate the underlying molecular mechanisms, differentiated THP-1 cells are cultured in a medium containing Kahweol for 12 h prior to LPS exposure, yielding consistent findings with the in vivo results. Moreover, AMPK inhibitors abrogate the above effects, indicating Kahweol acts in an AMPK-dependent manner. Furthermore, the study explores how Kahweol activates AMPK and finds that this process is mediated by CamKK II. CONCLUSION: Pretreatment with Kahweol attenuates sepsis-induced acute lung injury via improving mitochondrial homeostasis in a CaMKKII/AMPK-dependent pathway and may be a potential candidate to prevent sepsis-induced ALI.

Single-cell RNA sequencing analysis revealed cellular and molecular immune profiles in lung squamous cell carcinoma.

Although breakthroughs have been made in the treatment of non-small cell lung cancer, there are only a few choices for advanced-stage or recurrent lung squamous cell carcinoma (LUSC) patients. In our study, we identified 7 major cell types in thedepicted the immunolandscape of LUSC microenvironment using single-cell RNA sequencing. We found that an immunosuppressive receptor, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), was highly expressed by regulatory T cells (Tregs) and exhausted CD8+T cells, suggesting that upregulation of TIGIT might promote an immunosuppressive microenvironment and inhibit the cytotoxic ability of CD8+T cells. We also identified tumor-associated neutrophil (TAN), characterized by CXCR2, CSF3R and CXCL8, in the tumor region, and TANs upregulated the expression of interleukin 1 receptor antagonist (IL1RN) which suggested that TAN might exert an immunosuppressive role via expressing IL1RN. Furthermore, the number of SPP1+ macrophages(SPP1+M) significantly increased in tumor microenvirnment, which was correlated with the poor survival of patients. Additionally, regulatory networks based on SPP1+M revealed that the disparities of several ligand-receptor pairs existed between tumor and normal tissues. Among these pairs, SPP1-CD44 showed the most interactions between SPP1+M and other cell types. Our results provided deep insight into the immune landscape of LUSC and an essential resource for drug discovery in the future.

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury.

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.

Inflammatory Caspases Drive Pyroptosis in Acute Lung Injury.

Acute lung injury (ALI), a critical respiratory disorder that causes diffuse alveolar injury leads to high mortality rates with no effective treatment. ALI is characterized by varying degrees of ventilation/perfusion mismatch, severe hypoxemia, and poor pulmonary compliance. The diffuse injury to cells is one of most important pathological characteristics of ALI. Pyroptosis is a form of programmed cell death distinguished from apoptosis induced by inflammatory caspases, which can release inflammatory cytokines to clear cells infected by pathogens and promote monocytes to reassemble at the site of injury. And pyroptosis not only promotes inflammation in certain cell types, but also regulates many downstream pathways to perform different functions. There is increasing evidence that pyroptosis and its related inflammatory caspases play an important role in the development of acute lung injury. The main modes of activation of pyroptosis is not consistent among different types of cells in lung tissue. Meanwhile, inhibition of inflammasome, the key to initiating pyroptosis is currently the main way to treat acute lung injury. The review summarizes the relationship among inflammatory caspases, pyroptosis and acute lung injury and provides general directions and strategies to conduct further research.

Mangiferin Mitigates Lipopolysaccharide-Induced Lung Injury by Inhibiting NLRP3 Inflammasome Activation.

SCOPE: Mangiferin (MF) is a natural phytopolyphenol, which displays potential pharmacological properties involving antibacterial, anti-inflammation, antioxidant and anti-tumor. However, little is known about the roles of MF in lung injury. The aim of this study is to demonstrate the modulatory effects and molecular mechanisms by which MF operates in sepsis-induced lung injury. METHODS AND RESULTS: To examine the protective properties of MF, an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice and an in vitro model of LPS-treated J774A.1 cells were established, respectively. The results revealed that MF treatment significantly relieved LPS-induced pathological injury and inflammatory response in murine lung tissues. Meanwhile, MF treatment also inhibited nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation and pyroptosis induced by LPS. In macrophage-specific NLRP3 deficiency mice treated with LPS, MF showed little protective effects. NLRP3 overexpression by adenovirus could also offset the beneficial effects of MF in LPS-treated J774A.1 cells. Furthermore, we found that MF could suppress the expression of NLPR3 and pyroptosis of macrophages by inhibiting the nuclear translocation of the nuclear factor-κB (NF-κB) subunits P50 and P65. CONCLUSION: MF protects against lung injury and inflammatory response by inhibiting NLRP3 inflammasome activation in a NF-κB-dependent manner in macrophages, which provides a promising therapeutic candidate for the treatment of lung injury.

Ferroptosis: A New Promising Target for Lung Cancer Therapy.

Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.

The Prognostic Significance of the Histological Types in Patients With Nonsmall Cell Lung Cancer ≤2 cm.

Background: Few studies attempt to investigate the impact of histology on the outcome of nonsmall-cell lung cancer (NSCLC) patients. In this study, we aim to determine whether the type of histology influenced the outcome of stage IA NSCLC patients with tumor size (TS) ≤20 mm. Methods: The data of the population in our study was collected from the Surveillance, Epidemiology, and End Results (SEER) program, which is supported by the National Cancer Institute of the United States. The primary outcome was overall survival (OS). Cox-regression proportional hazards models were performed to identify prognostic factors for OS. The secondary outcome was lung cancer-specific mortality (LCSM). A competing risk model was used to identify risk factors associated with LCSM. Results: A total of 4,424 eligible patients (T1a-bN0M0) who received sublobar resection [wedge resection (WR) and segmentectomy] were identified and included in the study for further analysis. For patients with TS ≤ 10 mm, multivariate Cox-regression analyses for OS showed that lung squamous cell carcinoma (LUSC) yielded poorer OS compared with lung adenocarcinoma (LUAD), and no difference was observed between LUSC and LUAD for LCSM in competing risk models. For patients with TS > 10 and ≤20 mm, multivariate analyses revealed that LUSC patients experienced poorer OS compared with that of LUAD; the univariate competing risk analysis indicated SCC pathology predicted an increased risk of death from lung cancer, whereas no difference is observed in the multivariate competing analysis. In addition, segmentectomy was associated with longer OS in patients with >10 and ≤20 mm but not in patients with ≤10 mm compared with WR. Conclusion: Our study demonstrated that squamous pathology was associated with the worse OS but not LCSM for patients with ≤20 mm compared with adenocarcinoma. Moreover, segmentectomy when compared to wedge resection appears to be associated with a better prognosis in patients with neoplasm >10 mm, but not in the case of nodule ≤10 mm.