Search Results (40)

Anaplastic thyroid cancer (ATC) is among the most lethal human malignancies, characterized by rapid progression, therapeutic resistance, and a median survival of less than one year. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have limited effect, and targeted or immune-based treatments provide only transient benefit. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a therapeutic vulnerability in ATC. This review synthesizes current evidence on ferroptosis biology, preclinical validation, and therapeutic implications in ATC. Genomic alterations such as TP53, BRAF^V600E, RAS, and PIK3CA converge on redox imbalance and metabolic rewiring, rendering ATC cells dependent on antioxidant defenses. Dysregulated iron homeostasis through ferritinophagy and HO-1 activity, together with lipid remodeling via ACSL4 and LPCAT3, further sensitizes ATC to ferroptosis. Preclinical studies show that pharmacological inducers, including vitamin C, tenacissoside H, neferine, curcumin, and shikonin, as well as targeted agents such as dabrafenib and anlotinib, can trigger or synergize with ferroptosis. Genetic regulators, including SIRT6, the GPR34–USP8 axis, and the EIF3H–β-catenin pathway, modulate ferroptosis sensitivity, while RON receptor signaling links glycolysis to ferroptosis resistance. Combination regimens provide further translational potential. Nanoplatforms also offer innovative delivery strategies. Therapeutic approaches include initiating ferroptosis through iron and PUFA enrichment, disabling defenses such as GPX4 and Nrf2, and integrating ferroptosis inducers with existing modalities. Although systemic toxicity and resistance remain obstacles, biomarker-driven selection and drug repurposing offer promise. Ferroptosis represents a mechanistically distinct and clinically exploitable pathway for ATC. Full article

Cerebral ischemic reperfusion injury (CIRI) induces irreversible neurological dysfunction with high morbidity and mortality, yet effective clinical interventions remain limited. This study focused on ferroptosis in CIRI and explored the neuroprotective components and mechanisms of Pomelo peel essential oil (PPEO)—a product derived from Guangxi’s characteristic Shatian pomelo. Sprague-Dawley rats were used to establish two CIRI models: focal CIRI via Middle Cerebral Artery Occlusion (MCAO) and global CIRI via Cardiac Arrest/Cardiopulmonary Resuscitation (CA/CPR). Analyses were conducted using metabolomics, transcriptomics, histopathological staining, biochemical assays, RT-qPCR, Western blotting (WB), and molecular docking. Metabolomic results showed altered lipid-related metabolites in both models, predominantly unsaturated fatty acids and components of the arachidonic acid (AA) metabolic pathway. Transcriptomic analysis revealed significant upregulation of PTGS1/2 in the MCAO model. Nootkatone and β-pinene improved neuronal morphology, increased glutathione peroxidase 4 (GPX4) levels, and enhanced neurological scores. Notably, Nootkatone exhibited strong binding affinity to ALOX15, and reduced lipid metabolic disturbances in the CA/CPR model. AA metabolism varies with CIRI severity: it is inflammation-driven in focal CIRI and ferroptosis-associated in global CIRI. As a key component of PPEO, Nootkatone antagonizes ferroptosis via the ACSL4-LPCAT3-ALOX15 axis, offering a novel therapeutic target for global CIRI after CA/CPR. Full article

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a pivotal vulnerability in oral squamous cell carcinoma (OSCC). This review provides an overview of ferroptosis mechanisms and their implications for OSCC pathobiology and therapy. OSCC cells exhibit heightened reliance on anti-ferroptotic defenses such as GPX4, SLC7A11, FSP1, and Nrf2, and disrupting these pathways suppresses tumor growth and restores sensitivity to chemotherapy, radiotherapy, and immunotherapy. Genetic and epigenetic regulators, including p53, PER1, circ_0000140, and STARD4-AS1, critically modulate ferroptotic sensitivity, while metabolic enzymes such as ACSL4, LPCAT3, and TPI1 link ferroptosis to cellular plasticity and resistance. Preclinical studies highlight the promise of small-molecule inhibitors, repurposed agents (e.g., sorafenib, artesunate, trifluoperazine), natural compounds (e.g., piperlongumine, Evodia lepta, quercetin), and nanomedicine platforms for targeted ferroptosis induction. We further address ferroptosis within the tumor microenvironment, highlighting its immunogenic and context-dependent dual roles, and summarize genomic and transcriptomic evidence linking ferroptosis-related genes to patient prognosis. Beyond cancer, ferroptosis also contributes to non-malignant oral diseases, including pulpitis, periodontitis, and infection-associated inflammation, where inhibitors may protect tissues. Despite these advances, clinical translation is constrained by the lack of safe ferroptosis inducers and validated biomarkers. Future research should focus on developing pharmacologically viable GPX4 inhibitors, refining biomarker-driven patient stratification, and designing multimodal regimens that combine ferroptosis induction with standard therapies while preserving immune and tissue integrity. Ferroptosis therefore represents both a mechanistic framework and a translational opportunity to reshape oral oncology and broader oral disease management. Full article

Lipopolysaccharide (LPS) triggers oxidative damage in sheep hepatocytes, linked to ferroptosis. Ferulic acid (FA) is known for its antioxidative properties, but its protective role against LPS via ferroptosis regulation was unclear. The objective of this research is to explore the protective role of FA in mitigating LPS-induced oxidative stress in sheep hepatocytes. The experimental setup consisted of three groups: a control group, an LPS group treated with 10 µg/mL of LPS, and FA group that received both 10 µg/mL of LPS and 750 µg/mL of FA. We found that FA treatment decreased in contents of MDA and LDH. Metabolomics revealed that LPS affected glycerophospholipid metabolism, unsaturated fatty acids biosynthesis, ferroptosis, and arachidonic acid metabolism mainly by reducing the level of PUFAs and LPC in the hepatocyte supernatant, while FA affected glutathione metabolism by increasing L-cysteine, L-ornithine, L-glutamic acid, and L-glutamine. Moreover, transcriptomics demonstrated that the comparison of LPS and control groups were mainly enriched in arachidonic acid metabolism, glycerophospholipid metabolism, and ferroptosis, the comparison of FA and LPS groups was mainly enriched in glutathione metabolism. The results further confirmed the findings in the metabolomics and transcriptomics analyses, showing that LPS treatment upregulated the mRNA expression of ACSL4, LPCAT3, ALOX15, STEAP3, GPX4, GCLC, and GCL in hepatocytes, while reducing GSH and GR levels. In contrast, FA intervention attenuated LPS-induced iron overload by decreasing Fe²⁺ accumulation and suppressing the mRNA expression of ACSL4, LPCAT3, STEAP3, and ALOX15. Furthermore, FA enhanced the expression of GPX4, GCLC, GCLM, and restored GSH content in LPS-exposed hepatocytes. The above results demonstrated that the protective effect of FA on LPS-induced oxidative damage in the sheep hepatocytes was achieved by activating the GSH-GPX4 pathway and inhibiting lipid metabolism-mediated ferroptosis. Full article

Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the LPCAT1*rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. Methods: The LPCAT1 (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the LPCAT1 gene was elucidated using bioinformatic approaches. Results: The LPCAT1*rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, p = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, p = 0.416). Apgar score and Silverman–Andersen respiratory severity score (RSS) were statistically significant with prematurity classes (p < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. Conclusions: This research exhibited a significant difference between the LPCAT1 (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates. Full article

BEL1-like homeodomain protein 3 (BLH3) plays a crucial role in plant development. However, its involvement in the salt stress response has not been studied. In this study, we investigated the molecular mechanism underlying the response of LpBLH3 to salt stress in Lilium pumilum (L. pumilum) using various techniques, including quantitative PCR (RT-qPCR), determination of physiological indices of plant after Saline-Alkali stress, yeast two-hybrid screening, luciferase complementation imaging (LCI), and chromosome walking to obtain the promoter sequence, analyzed by PlantCARE, electrophoretic mobility shift assay (EMSA), and then dual-luciferase reporter assay(LUC). RT-qPCR analysis revealed that LpBLH3 is most highly expressed in the leaves of L. pumilum. The expression of LpBLH3 peaks at 24 or 36 h in the leaves under different saline stress. Under various treatments, compared to the wild type (WT), the LpBLH3 overexpression lines exhibited less chlorosis and leaf curling and stronger photosynthesis. The overexpression of LpBLH3 can enhance lignin accumulation in root and stem by positively modulating the expression of crucial genes within the lignin biosynthesis pathway. Y2H and LCI analyses demonstrated that LpBLH3 interacts with LpKNAT3. Additionally, EMSA and LUC analyses confirmed that LpBLH3 can bind to the promoter of LpABI5 and upregulate the expression of ABI5 downstream genes (LpCAT1/LpATEM/LpRD29B). In summary, LpBLH3 enhances the plant’s salt tolerance through the ABA pathway and lignin synthesis. This study can enrich the functional network of the BLH transcription factor family, obtain Lilium pumilum lines with good saline-alkali resistance, expand the planting area of Lilium pumilum, and improve its medicinal and ornamental values. Additionally, the functional analysis of the BLH transcription factor family provides new insights into how crops adapt to the extreme growth environment of saline-alkali soils. Full article

Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a key player in the pathogenesis of gastrointestinal (GI) diseases. Unlike apoptosis or necrosis, ferroptosis is characterized by distinctive metabolic and molecular pathways, including dysregulated iron metabolism, oxidative stress, and impaired antioxidant defenses. This review explores the complex role of ferroptosis in conditions such as inflammatory bowel disease (IBD), non-alcoholic steatohepatitis (NASH), and gastrointestinal cancers. Special attention is given to the molecular mechanisms underlying ferroptosis, including the Xc⁻/GSH/GPX4 axis, ferritinophagy, ACSL4/LPCAT3-mediated lipid remodeling, and the influence of the gut microbiota. Therapeutic strategies targeting ferroptosis—including pharmacological inhibitors, iron chelators, and microbiota-based interventions—are evaluated for their translational potential, underscoring ferroptosis as a promising target for precision therapies in gastroenterology and highlighting the need for further clinical studies to validate its diagnostic and therapeutic implications. Full article

Guanidinoacetic acid (GAA) has been used in ruminant feeding, but it is still unclear whether the exogenous addition of methyl donors, such as methionine (Met), can enhance the effects of GAA. This study investigated the effects of dietary GAA alone or combined with Met on beef cattle growth performance and explored the underlying mechanisms via blood analysis, liver metabolomics, and transcriptomics. Forty-five Simmental bulls (453.43 ± 29.05 kg) were assigned to three groups for 140 days: CON (control), GAA (0.1% GAA), and GAM (0.1% GAA + 0.1% Met), where each group consisted of 15 bulls. Compared with the CON group, the average daily gain (ADG) and feed conversion efficiency (FCE) of the two feed additive groups were significantly increased, and the digestibility of neutral detergent fiber (NDF) was improved (p < 0.05). Among the three treatment groups, the GAM group showed a higher rumen total volatile fatty acids (TVFAs) content and digestibility of dry matter (DM) and crude protein (CP) in the beef cattle. The serum indices showed that the contents of indicators related to protein metabolism, lipid metabolism, and creatine metabolism showed different increases in the additive groups (p < 0.05). It is worth noting that the antioxidant indexes in the serum and liver tissues of beef cattle in the two additive groups were significantly improved (p < 0.05). The liver metabolites related to protein metabolism (e.g., L-asparagine, L-glutamic acid) and lipid metabolism (e.g., PC (17:0/0:0)) were elevated in two additive groups, where Met further enhanced the amino acid metabolism in GAM. In the two additive groups, transcriptomic profiling identified significant changes in the expression of genes associated with protein metabolism (including PIK3CD, AKT3, EIF4E, HDC, and SDS) and lipid metabolism (such as CD36, SCD5, ABCA1, APOC2, GPD2, and LPCAT2) in the hepatic tissues of cattle (p < 0.05). Overall, the GAA and Met supplementation enhanced the growth performance by improving the nutrient digestibility, serum protein and creatine metabolisms, antioxidant capacity, and hepatic energy and protein and lipid metabolisms. The inclusion of Met in the diet was shown to enhance the nutrient digestibility and promote more efficient amino acid metabolism within the liver of the beef cattle. Full article

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, defined by intestinal epithelial cell death. While ferroptosis and disulfidptosis have been linked to IBD pathogenesis, the functional significance of disulfidptosis-related ferroptosis genes (DRFGs) in this disease remains poorly characterized. This investigation sought to pinpoint DRFGs as diagnostic indicators and clarify their mechanistic contributions to IBD progression. Methods: Four IBD datasets (GSE65114, GSE87473, GSE102133, and GSE186582) from the GEO database were integrated to identify differentially expressed genes (DEGs) (|log2FC| > 0.585, adj. p < 0.05). A Pearson correlation analysis was used to link disulfidptosis and ferroptosis genes, followed by machine learning (LASSO and RF) to screen core DRFGs. The immune subtypes and single-cell sequencing (GSE217695) results were analyzed. A DSS-induced colitis Mus musculus (C57BL/6) model was used for validation. Results: Transcriptomic profiling identified 521 DEGs, with 16 defined as DRFGs. Nine hub genes showed diagnostic potential (AUC: 0.71–0.91). Functional annotation demonstrated that IBD-associated genes regulate diverse pathways, with a network analysis revealing their functional synergy. The PPI networks prioritized DUOX2, NCF2, ACSL4, GPX2, CBS, and LPCAT3 as central hubs. Two immune subtypes exhibited divergent DRFG expression. Single-cell mapping revealed epithelial/immune compartment specificity. The DSS-induced murine colitis model confirmed differential expression patterns of DRFGs, with concordant results between qRT-PCR and RNA-seq, emphasizing their pivotal regulatory roles in disease progression and potential for translational application. Conclusions: DRFGs mediate IBD progression via multi-signal pathway regulation across intestinal cell types, demonstrating diagnostic and prognostic potential. Full article

Background: Bacterial infections are a major challenge in food processing and public health, and there is an urgent need to develop novel antimicrobial agents. Objectives: The purpose of this study is to investigate the potential mechanism and key components of Pinctada martensii antimicrobial proteins (Pm-Aps) to provide a theoretical basis for the development of novel antimicrobial agents. Methods: The researchers used Vibrio parahaemolyticus (VP) to stimulate Pinctada martensii, extracted the antimicrobial proteins, and analyzed their antimicrobial activities, potential mechanisms of action, and key components using proteomics. Results: The results showed that the antimicrobial activity of Pm-Aps, with broad-spectrum antimicrobial effects, was significantly enhanced after VP stimulation. This was associated with the upregulation of LAAO, CHDH, TLR2, ATG16L1, BAK, CLCA4, and CASP8 and the downregulation of MCM3, MCM5, DTYMK, PLK1, FBXO6, LPCAT3, GST, LAMTOR5, CYP17A, CTSA, and RRM1. It is hypothesized that these proteins may inhibit bacterial growth and multiplication by activating immune-related signaling pathways, inhibiting DNA replication and repair, and inducing apoptosis and autophagy. Furthermore, it was found that LAAO may be a key component of the antimicrobial action of Pm-Aps, killing bacteria by catalyzing the oxidation of amino acids to produce hydrogen peroxide (H₂O₂). Conclusions: These results strongly suggest that Pm-Aps is an effective antimicrobial protein, and it is expected that new LAAO can be obtained from Pm-Aps. Full article

Angiotensin II (Ang II) is an effective vasoconstriction peptide, a major effector molecule of the renin–angiotensin–aldosterone system (RAAS) and one of the important causes of endothelial dysfunction. Ferroptosis is considered to be involved in the occurrence and development of cardiovascular diseases. This study is dedicated to exploring the role and mechanism of Ang II-induced ferroptosis in HUVECs and to finding molecular targets for vascular endothelial injury and dysfunction during the progression of hypertension. In this study, we found that with the increase in exposure concentration, the intracellular ROS content and apoptosis rate increased significantly, the NO release decreased significantly in the medium- and high-concentration groups and the ET-1 content in the high-concentration group increased significantly. The expression of ZO-1 protein was significantly decreased in the high-concentration group. The expression of p-eNOS, VE-cadherin and Occludin protein showed a dose-dependent downward trend, while the ICAM-1 protein showed an upward trend. Ang II caused lipid metabolism disorders in HUVECs, and the PL–PUFAs associated with ferroptosis were significantly increased. In addition, Ang II promoted a significant increase in intracellular free Fe²⁺ content and MDA and a significant decrease in GSH content. Furthermore, the expression of GPX4, SLC7A11 and SLC3A2 was down-regulated, the expression of ACSL4, LPCAT3 and ALOX15 was up-regulated, and the ratio of p-cPLA2/cPLA2 was increased. After the intervention of ferroptosis inhibitor Fer-1, the injury and dysfunction of HUVECs induced by Ang II were significantly rescued. Immunofluorescence results showed that the expression of CD36 showed a significant increasing trend and was localized in the cytoplasm. Over-expression of CD36 promoted Ang II-induced ferroptosis and endothelial dysfunction. In conclusion, Ang II induces the injury of HUVECs, decreases vascular diastole and endothelial barrier-related molecules, and increases vascular constriction and adhesion-related molecules, which may be related to CD36 and its mediated lipid peroxidation and ferroptosis signals. Full article

The present study aimed to investigate whether supplementation of modified lysophospholipids (LPLs) in the diet of broiler breeders can benefit their offspring. A total of 264 49-week-old breeders (Ross 308) were allocated and fed based on a 2 × 2 factorial arrangement with two levels of dietary energy (normal energy = 2800 kcal/kg and low energy = 2760 kcal/kg) and two LPL levels (0 and 0.5 g/kg) for periods of 8 and 12 weeks. The offspring were assessed for growth performance, serum parameters, hepatic antioxidative capability, and expression of genes involved in liver β-oxidation at 7 days old. The LPL inclusion improved (p < 0.01) average body weight (ABW), average daily gain (ADG), and feed conversion ratio (FCR). The offspring of 61-week-old breeders fed with LPL exhibited reduced serum triglyceride levels (p < 0.01) but an increase in hepatic glutathione peroxidase (p < 0.05). The LPL increased (p < 0.001) the mRNA expression of the PGC-1α gene in the liver. Supplementing LPL in low-energy diets resulted in higher FABP1 gene expression (p < 0.05) in the intestine. In conclusion, LPL supplementation in the breeders’ diet improved offspring performance by enhancing fatty acid absorption, hepatic indices, and the expression of genes involved in liver β-oxidation. Full article

Heat stress (HS) is a significant concern in broiler chickens, which is vital for global meat supply in the dynamic field of poultry farming. The impact of heat stress on the ileum and its influence on the redox homeostatic genes in chickens remains unclear. We hypothesized that adding zinc to the feed of heat-stressed broilers would improve their resilience to heat stress. However, this study aimed to explore the effects of organic zinc supplementation under HS conditions on broiler chickens’ intestinal histology and regulation of HS index genes. In this study, 512 Xueshan chickens were divided into four groups: vehicle, HS, 60 mg/kg zinc, and HS + 60 mg/kg zinc groups. Findings revealed that zinc supply positively increased the VH and VH: CD in the ileum of the broilers compared to the HS group, while CD and VW decreased in Zn and HS+Zn supplemented broilers. Zn administration significantly increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and decreased the enzymatic activities of reactive oxygen species (ROS) and malondialdehyde (MDA) compared to the HS group. In addition, Zn administration significantly increased relative ATP, complex I, III, and V enzyme activity compared to the HS group. Furthermore, the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), lactate transporter 3 (LPCAT3), peroxiredoxin (PRX), and transferrin receptor (TFRC) in the protein levels was extremely downregulated in HS+Zn compared to the HS group. Zn supply significantly decreased the enrichment of RORγ, P300, and SRC1 at target loci of ACSL4, LPCAT3, and PRX compared to the HS group. The occupancies of histone active marks H3K9ac, H3K18ac, H3K27ac, H3K4me1, and H3K18bhb at the locus of ACSL4 and LPCAT3 were significantly decreased in HS+Zn compared to the HS group. Moreover, H3K9la and H3K18la at the locus of ACSL4 and LPCAT3 were significantly decreased in HS+Zn compared to the HS group. This study emphasizes that organic Zn is a potential strategy for modulating the oxidative genes ACSL4, LPCAT3, PRX, and TFRC in the ileum of chickens via nuclear receptor RORγ regulation and histone modifications. Full article

Dissecting the genetics of production traits in livestock is of outmost importance, both to understand biological mechanisms underlying those traits and to facilitate the design of selection programs incorporating that information. For the pig industry, traits related to curing are key for protected designation of origin productions. In particular, appropriate ham weight loss after dry-curing ensures high quality of the final product and avoids economic losses. In this study, we analyzed data (N = 410) of ham weight loss after approximately 20 months of dry-curing. The animals used for ham production were purebred pigs belonging to a commercial line. A genome-wide association study (GWAS) of 29,844 SNP markers revealed the polygenic nature of the trait: 221 loci explaining a small percentage of the variance (0.3–1.65%) were identified on almost all Sus scrofa chromosomes. Post-GWAS analyses revealed 32 windows located within regulatory regions and 94 windows located in intronic regions of specific genes. In total, 30 candidate genes encoding receptors and enzymes associated with ham weight loss (MTHFD1L, DUSP8), proteolysis (SPARCL1, MYH8), drip loss (TNNI2), growth (CDCA3, LSP1, CSMD1, AP2A2, TSPAN4), and fat metabolism (AGPAT4, IGF2R, PTDSS2, HRAS, TALDO1, BRSK2, TNNI2, SYT8, GTF2I, GTF2IRD1, LPCAT3, ATN1, GNB3, CMIP, SORCS2, CCSER1, SPP1) were detected. Full article

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation, affecting physiological and pathological processes. Fatty liver disease associated with metabolic dysfunction is a common pathological condition in aquaculture. However, the exact role and mechanism of ferroptosis in its pathogenesis and progression remains unclear. In this study, an experiment was conducted using different dietary lipid levels in the feeding of largemouth bass (Micropterus salmoides) for 11 weeks. The results revealed that the growth performance and whole-body protein content significantly increased with the elevation of dietary lipid levels up to 12%. The activities of antioxidant enzymes as well as the content of GSH (glutathione) in the liver initially increased but later declined as the lipid levels increased; the contents of MDA (malondialdehyde) and GSSG (oxidized glutathione) demonstrated an opposite trend. Moreover, elevating lipid levels in the diet significantly increased liver Fe²⁺ content, as well as the expressions of TF (Transferrin), TFR (Transferrin receptor), ACSL4 (acyl-CoA synthetase long-chain family member 4), LPCAT3 (lysophosphatidylcholine acyltransferase 3), and LOX12 (Lipoxygenase-12), while decreasing the expressions of GPX4 (glutathione peroxidase 4) and SLC7A11 (Solute carrier family 7 member 11). In conclusion, the optimal lipid level is 12.2%, determined by WG-based linear regression. Excess lipid-level diets can up-regulate the ACSL4/LPCAT3/LOX12 axis, induce hepatic oxidative stress and cell death through a ferroptotic-like program, and decrease growth performance. Full article