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Lung cancer is the leading cause of cancer death, and it is widely accepted that chronic inflammation is an important risk for the development of lung cancer. Now, it is recognized that the nucleotide-binding and oligomerization domain (NOD) like receptors (NLRs)-containing inflammasomes are involved in cancer-related inflammation. This study was designed to investigate the effects of NLR family pyrin domain containing protein 3 (NLRP3) inflammasome on the proliferation and migration of lung adenocarcinoma cell line A549. Using 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, scratch assay, and Transwell migration assay, we showed that activation of the NLRP3 inflammasome by LPS+ATP enhanced the proliferation and migration of A549 cells. Western blot analysis showed that activation of phosphorylation of Akt, ERK1/2, CREB and the expression of Snail increased, while the expression of E-cadherin decreased after the activation of NLRP3 inflammasome. Moreover, these effects were inhibited by the following treatments: i) down-regulating the expression of NLRP3 by short hairpin RNA (shRNA) interference, ii) inhibiting the activation of NLRP3 inflammasome with a caspase-1 inhibitor, iii) blocking the interleukin-1β (IL-1β) and IL-18 signal transduction with IL-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18BP). Collectively, these results indicate that NLRP3 inflammasome plays a vital role in regulating the proliferation and migration of A549 cells and it might be a potential target for the treatment of lung cancer.

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

Background Non-small cell lung cancer is a heterogeneous disease driven by extensive molecular alterations. Exosomes are small vesicles with diameters ranging from 30 to 150 nm released by various cell types and are important mediators of information transmission in tumor cells. Exosomes contain proteins, lipids, and various types of nucleic acids, including miRNAs and even DNA and RNA. MFI2 Antisense RNA 1 (MFI2-AS1) is a long noncoding RNA known to promote cell proliferation, metastasis and invasion in a variety of malignancies. Methods The relative expression of MFI2-AS1 in NSCLC tissues was examined using RNA fluorescence in situ hybridization (FISH) staining. Transwell migration and wound healing assays were used to analyze cell migration and invasion abilities. Tube formation is used to assess angiogenic capacity. CCK8 was used to assess cell proliferation ability. RNA immunoprecipitation (RIP) experiments confirmed that MFI2-AS1 acts as a competing endogenous RNA (ceRNA) for miR-107. Dual-luciferase reporter assays were used to identify potential binding between MFI2-miRNA and target mRNA. In vivo experiments were performed by injecting exosomes into subcutaneous tumors to establish animal models. Result Exosomal MFI2-AS1 increases NFAT5 expression by sponging miR-107, which in turn activates the PI3K/AKT pathway. We found that the MFI2-AS1/miR-107/NFAT5 axis plays an important role in exosome-mediated NSCLC progression, is involved in pre-metastatic niche formation, and can be used as a blood-based biomarker for NSCLC metastasis. Conclusion We demonstrate that MFI2-AS1 is upregulated in exosomes secreted by metastatic NSCLC cells and can be transferred to HUVECs, promoting angiogenesis and migration.

Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the leading cause of end-stage renal disease worldwide. The pathogenesis of DN is complex, and oxidative stress and ferroptosis play key roles. Petunidin (PET) is a member of the anthocyanin family and has strong antioxidant activity. However, there are no relevant studies on the use of PET to improve diabetic nephropathy. The aim of this study was to investigate the protective mechanism of PET in diabetic nephropathy. In the animal experiments, db/m and db/db mice were treated with PET for 8 weeks. Renal function, urinary albumin/urinary creatinine ratio (ACR) and renal tissue section staining were used to observe renal pathological injury. For the cell experiments, normal renal cortex proximal convoluted tubule epithelial cells (HK-2 cells) were selected for further verification, and ADV-mediated Keap1 and mitoNQO1 overexpression models were constructed. Western blotting, immunofluorescence and TUNEL staining were used to detect oxidative stress- and ferroptosis pathway-related indicators. Keap1 expression in the kidneys of db/db mice was significantly increased, along with reduced mitochondrial translocation of NQO1, while PET reversed this trend to decrease oxidative stress and inhibit ferroptosis. Further experiments confirmed that after overexpression of Keap1, the protective effect of PET in high glucose-induced HK2 cells disappeared, whereas overexpression of mitoNQO1 reduced oxidative stress and ferroptosis in a mitochondria-dependent way.

To explore the benefits of oligosaccharides (MOO) on ischemia-reperfusion (I/R) injury and the possible mechanisms involved. Myocardial I/R injury were induced by left anterior descending branch ligation. MOO pretreatment was given orally 2 weeks prior to ischemic treatment. Echocardiograms, biochemical parameters, and histological and immunohistochemical analyses were used to determine the benefits of MOO on myocardial I/R injury. Oxidative stress and ferroptosis were examined by biochemical parameters, Western blot, immunohistochemistry, and Tunel staining. MOO improved cardiac function and reduced myocardial oxidative stress and ferroptosis, which was associated with the inhibition of NADPH Oxidase 4 (NOX4) expression. Whereas, the upregulation of NOX4 abolished the benefits of MOO. Furthermore, MOO enhanced mitochondrial superoxide dismutase 2 (SOD2) activity and stimulated the mitochondrial translocation of glutathione peroxidase 4 (mitoGPX4) by inhibiting NOX4. Mitochondria-specific GPX4 overexpression attenuated mitochondrial oxidative stress and suppressed mitochondria-associated ferroptosis in cardiomyocytes that suffered from hypoxia-reoxygenation (H/R) injury, even after NOX4 overexpression. These results indicate the beneficial effects of MOO on myocardial I/R injury by suppressing oxidative stress and mitochondria-associated ferroptosis through NOX4/mitoGPX4 pathway.

This study aims to investigate the benefits of gypensapogenin I (GI) on myocardial ischemia-reperfusion injury (MIRI) and the underlying mechanisms. An MIRI model was established by ligating the anterior descending coronary artery (LAD) followed by blood flow restoration in mice. Cardiac dysfunction and myocardial infarction size were evaluated by echocardiography and triphenyltetrazolium chloride (TTC) staining. PANoptosis, ferroptosis, and mitochondrial redox state were examined by immunofluorescence, Western blotting, and an ELISA kit. In addition, molecular and biochemical methods were applied to illustrate the exact mechanisms of GI on MIRI. GI pretreatment alleviated cellular oxidative stress, inhibited PANoptosis and ferroptosis, reduced myocardial infarction area, and improved cardiac function during MIRI. Further results revealed that mitochondrial biogenesis and the anti-oxidative system were impaired in mice suffering from MIRI, and these effects were significantly alleviated by GI treatment via downregulation of the NADPH oxidase 2 (NOX2) level. Moreover, NOX2 promoted mitochondrial dysfunction by suppressing the AMP-activated protein kinase (AMPK)-PGC-1α-Sirt3 signaling pathway. In addition, the NOX2 activator exacerbated oxidative damage and offset all the beneficial effects of GI on mitochondrial function, PANoptosis, and ferroptosis. Meanwhile, reinforced AMPK phosphorylation by GI or AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) maintained the mitochondrial redox state and biogenesis and suppressed PANoptosis and ferroptosis. GI pretreatment protected the cardiomyocytes from MIRI-induced PANoptosis and ferroptosis by maintaining the mitochondrial redox state and biogenesis through the modulation of the NOX2/AMPK signaling pathway. Our findings indicate that GI pretreatment could be a promising therapeutic agent for MIRI treatment.

Thioredoxin reductase 2 (TrxR2), a radical‐trapping antioxidant, plays a critical role in cardiac defense. However, the mechanisms underlying its benefits remain unclear. In this study, we aimed to investigate whether endothelial TrxR2 prevents cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Key genes in the thioredoxin family and those involved in ferroptosis were analyzed using bulk RNA‐sequencing assay. Diabetic injury was induced in multiple transgenic mouse models, including endothelial cell‐specific knockout mice for TrxR2, sterol carrier protein 2 (SCP2), and Tu translation elongation factor, mitochondrial (TUFM). The TrxR2 lactylation site was identified by mass spectrometry and verified by a custom‐made lactylation antibody. Mitochondrial thioredoxin reductase (mitoTrxR) activity and lipid peroxyl radicals were detected using fluorescence staining. Endothelial TrxR2 deficiency significantly suppressed mitoTrxR activity, exacerbated cardiac microvascular dysfunction, and accelerated DCM progression. In contrast, TrxR2 overexpression and Kukoamine B (TrxR2 agonist) treatment inhibited mitochondria‐associated ferroptosis by facilitating SCP2 degradation and blocking the mitochondrial translocation of acyl‐CoA synthetase long‐chain family member 4 (ACSL4) via mitophagy. Mechanistically, TrxR2 maintained TUFM expression by scavenging oxygen radicals, thereby facilitating the mitochondrial translocation of AMPK for mitophagy activation. TrxR2 undergoes lactylation at lysine 340. This process is mediated by mitochondrial alanyl‐tRNA synthetase 2 (AARS2) and lactate accumulation in both human and mouse diabetic hearts. This modification and sodium lactate administration compensatorily enhanced mitoTrxR activity, promoted mitophagy, and conferred ferroptosis resistance in cardiac microcirculation in DCM. Our findings demonstrate that TrxR2 and its lactylation modification promote mitophagy, enhance ferroptosis resistance, and improve cardiac microvascular function in DCM. Thus, this study provides a promising therapeutic approach for the management of diabetic complications. TrxR2 deletion in diabetic mice suppresses TUFM‐AMPK‐FUNDC1‐dependent mitophagy in endothelial cells, resulting in SCP2 upregulation and mitochondrial translocation of ACSL4. Mitochondrial ACSL4 promotes mitochondrial eicosanoid biosynthesis and ferroptosis, thereby aggravating cardiac microvascular injury and diabetic cardiomyopathy. Lactylation modification of TrxR2 in diabetes compensatorily enhances mitochondrial thioredoxin reductase activity, mitophagy, and ferroptosis resistance in endothelial cells, exerting cardiovascular protection.

Acute lung injury (ALI) is a prevalent critical condition for which effective treatments remain elusive. Ferroptosis plays a significant role in the pathophysiology of ALI. The deubiquitinating enzyme YOD1 is implicated in the regulation of infectious diseases; however, its specific role in ALI and ferroptosis is not yet fully understood. In this study, we observed that YOD1 expression was notably elevated in the lung tissue and primary alveolar type II (ATII) cells of mice subjected to lipopolysaccharide (LPS)-induced ALI. Moreover, YOD1 deficiency significantly mitigated ferroptosis and damage to the alveolar epithelial barrier. Mechanistically, YOD1 interacts directly with NCOA4 through its OTU domain, inhibiting K48-linked ubiquitination at the K343/K353 lysis residue of NCOA4, thus facilitating NCOA4-mediated autophagic degradation of FTH1 and promoting ferroptosis. Overall, our findings indicate that YOD1 regulates NCOA4 via deubiquitination, suggesting it may serve as a potential therapeutic target for ALI. This study reveals that the deubiquitinase YOD1 is upregulated in LPS-induced acute lung injury (ALI) and exacerbates ferroptosis by deubiquitinating and stabilizing NCOA4, thereby promoting NCOA4-mediated ferritinophagy. YOD1 deficiency alleviated lung injury, suggesting YOD1 as a potential therapeutic target for ALI.

A series of carbon nanotube (CNT)-supported monometallic Pd and bimetallic Pd–Fe catalysts were synthesized and employed for catalytic hydrogenolysis of cellulose into polyols, including hexitol, ethylene glycol (EG), 1,2-propanediol (1,2-PG), and glycerol (Gly). The physicochemical properties of the catalysts were characterized by nitrogen physical adsorption measurements, X-ray diffraction analysis, transmission electron microscopy, and X-ray photoelectron spectroscopy. The total yield of hexitol, EG, 1,2-PG, and Gly in hydrolytic hydrogenation of cellulose was 37, 55, and 53% for Pd/CNTs, Pd–Fe/CNTs (Pd:Fe = 1:1), and Pd–Fe/CNTs (Pd:Fe = 1:2), respectively. Addition of Fe to Pd significantly modified the physicochemical properties of the nanoparticles and their catalytic performance, especially regarding hexitol selectivity. The promoting effect of Fe, especially for hexitol selectivity, compared with the monometallic catalyst is due to the fact that incorporation of Fe may stabilize Pd 0 nanoparticles and lead to downshift of the d -band center of Pd metal nanoparticles by charge transfer from Fe to Pd. Recycling experimental results showed that leaching of Fe resulted in a significant decrease in the hexitol yield obtained using the Pd–Fe/CNTs after the first recycle, further demonstrating that Fe element plays a promoting role for hexitol formation.

Recent studies have highlighted the relationship between ferroptosis in type II alveolar epithelial cell (ATII cell) and acute lung injury (ALI). Solute carrier family 38 member 1 (SLC38A1) is a member of the SLC38 gene family, expressed in the lung, and plays a crucial role in cellular processes. To explore the beneficial effects of SLC38A1 on ATII cell damage in Acute lung injury (ALI) from the perspectives of ferroptosis. Acute lung injury was established by intratracheal administration of lipopolysaccharide (LPS) in C57BL/6 mice for 24 hours. SLC38A1 overexpression was attained via adeno- associated virus serotype 6 (AAV6) transfection. Primary type II alveolar epithelial cell (ATII cell) were transfected with lentiviral vectors (LV) encoding SLC38A1, DMT1, shSLC38A1, shULK1, and shHSP90. Lung damage was assessed by TUNEL staining and pathological staining. Protein expression and interactions were assessed by western blotting and immunoprecipitation. SLC38A1 overexpression alleviated LPS-induced injury and inflammation by inhibiting oxidative stress and mitochondrial dysfunction in mice and ATII cells. Further results demonstrated that SLC38A1 overexpression inhibited ferroptosis, which was derived from promoting the degradation of Divalent Metal Transporter 1 (DMT1). SLC38A1 promoted the interactions among DMT1, HSP90, HSC70 and Lamp-2a, enhanced the lysosomal translocation of DMT1, and thereby intensified the chaperone-mediated autophagy (CMA) of DMT1. DMT1 overexpression accentuated LPS-induced lung injury and ATII cells injury, but the effects were relieved by SLC38A1 overexpression. SLC38A1 promotes DMT1 degradation through CMA, thereby inhibiting ferroptosis and improving lung injury. Consequently, we propose that SLC38A1 might serve as a potential therapeutic target and early diagnostic marker for ALI.