Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach.

Mulberry is a common crop rich in flavonoids, and its leaves (ML), fruits (M), and branches (Ramulus Mori, RM) have medicinal value. In the present study, a total of 118 flavonoid metabolites (47 flavone, 23 flavonol, 16 flavonoid, 8 anthocyanins, 8 isoflavone, 14 flavanone, and 2 proanthocyanidins) and 12 polyphenols were identified by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. The most abundant in ML were 8-C-hexosyl-hesperetin O-hexoside and astragalin, the most abundant in M were 8-C-hexosyl-hesperetin O-hexoside and naringenin, and the most abundant in RM were cyanidin 3-O-galactoside and gallocatechin-gallocatechin. The total flavonoid compositions of ML and RM were essentially the same, but the contents of flavonoid metabolite in more than half of them were higher than those in M. Compared with ML, the contents of flavone and flavonoid in RM and M were generally down-regulated. Each tissue part had a unique flavonoid, which could be used as a marker to distinguish different tissue parts. In this study, the differences between flavonoid metabolite among RM, ML, and M were studied, which provided a theoretical basis for making full use of mulberry resources.

Erythroid-intrinsic activation of TLR8 impairs erythropoiesis in inherited anemia.

Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19+/- HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.

Liquid chromatography-tandem mass spectrometry in clinical laboratory protein measurement.

Proteins are essential components of human cells and tissues, and they are commonly measured in clinical laboratories using immunoassays. However, these assays have certain limitations, such as non-specificity binding, insufficient selectivity, and interference of antibodies. More sensitive, accurate, and efficient technology is required to overcome these limitations. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful analytical tool that provides high sensitivity and specificity, making it superior to traditional methods such as biochemical and immunoassays. While LC-MS/MS has been increasingly used for detecting small molecular analytes and steroid hormones in clinical practice recently, its application for protein or peptide analysis is still in its early stages. Established methods for quantifying proteins and peptides by LC-MS/MS are mainly focused on scientific research, and only a few proteins and peptides can be or have the potential to be detected and applied in clinical practice. Therefore, this article aims to review the clinical applications, advantages, and challenges of analyzing proteins and peptides using LC-MS/MS in clinical laboratories.

Clinical intervention effect of Xuefu Zhuyu decoction on chronic heart failure complicated with depression.

BACKGROUND: The diagnosis and treatment of depression in patients with chronic heart failure (CHF) is challenging, with no ideal treatment at present. AIM: To analyze the clinical intervention effect of Xuefu Zhuyu decoction (XFZYD) on CHF complicated with depression. METHODS: The study cohort comprised 116 patients with CHF complicated with depression who received treatment from July 2020 to July 2023, of which 55 received Western medicine (control group) and 61 received XFZYD (research group). Data on clinical effectiveness, traditional Chinese medicine (TCM) syndrome score, cardiac function, negative emotions, and serum inflammatory factors, were collected for comparative analyses. RESULTS: Compared with the control group, the research group had an evidently higher total effective rate. Furthermore, there were marked reductions in TCM symptom score, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, Self-Rating Depression Scale, Hamilton Depression Scale, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 in the research group after treatment, and these were lower than the corresponding values in the control group. Left ventricular ejection fraction was increased and higher in the research group compared with the control group after treatment. CONCLUSION: Our findings conclusively proved that XFZYD was considerably superior to Western medicine for treating CHF complicated with depression because it significantly alleviated patients' symptoms, improved cardiac function, relieved negative emotions, and reduced the levels of serum inflammatory factors.

Reduced expression of cathepsin F predicts poor prognosis in patients with clear cell renal cell carcinoma.

Abnormalities in the extracellular matrix (ECM) play important roles in the regulation and progression of clear cell renal cell carcinoma (ccRCC). The cysteine cathepsin is one of the major proteases involved in ECM remodeling and has been shown to be aberrantly expressed in multiple cancer types. However, the clinical significance and biological function of distinct cysteine cathepsins in ccRCC remain poorly understood. In this study, several bioinformatics databases, including UALCAN, TIMER, GEPIA and the Human Protein Atlas datasets, were used to analyze the expression and prognostic value of different cysteine cathepsin family members in ccRCC. We found that the expression level of CTSF was downregulated in tumor tissues and closely related to the poor survival of ccRCC patients. Further in vitro experiments suggested that CTSF overexpression suppressed the proliferation and migration of ccRCC cells. Moreover, the expression of CTSF was shown to be associated with several immune-infiltrating cells and immunomodulators in ccRCC. These results indicated that CTSF might be a promising diagnostic and prognostic marker in ccRCC.

Secondary Metabolites from Marine-Derived Fungus Penicillium rubens BTBU20213035.

Two new polyketide derivatives, penirubenones A and B (1 and 2), and two naturally rare amino-bis-tetrahydrofuran derivatives, penirubenamides A and B (3 and 4), together with nine known compounds (5-13) were isolated from the marine-derived fungus Penicillium rubens BTBU20213035. The structures were identified by HRESIMS and 1D and 2D NMR analyses, and their absolute configurations were determined by a comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy and 13C NMR data. We found that 6 exhibited antibacterial activity against Staphylococcus aureus, with an MIC value of 3.125 µg/mL, and 1 and 2 showed synergistic antifungal activity against Candida albicans at 12.5 and 50 µg/mL with 0.0625 µg/mL rapamycin.

Record-High T_{c} and Dome-Shaped Superconductivity in a Medium-Entropy Alloy TaNbHfZr under Pressure up to 160 GPa.

Superconductivity has been one of the focal points in medium and high-entropy alloys (MEAs-HEAs) since the discovery of the body-centered cubic (bcc) HEA superconductor in 2014. Until now, the superconducting transition temperature (T_{c}) of most MEA and HEA superconductors has not exceeded 10 K. Here, we report a TaNbHfZr bulk MEA superconductor crystallized in the BCC structure with a T_{c} of 15.3 K which set a new record. During compression, T_{c} follows a dome-shaped curve. It reaches a broad maximum of roughly 15 K at around 70 GPa before decreasing to 9.3 K at 157.2 GPa. First-principles calculations attribute the dome-shaped curve to two competing effects, that is, the enhancement of the logarithmically averaged characteristic phonon frequency ω_{log} and the simultaneous suppression of the electron-phonon coupling constant λ. Thus, TaNbHfZr MEA may have a promising future for studying the underlying quantum physics, as well as developing new applications under extreme conditions.

Screening of α-Glucosidase Inhibitors in Cichorium glandulosum Boiss. et Huet Extracts and Study of Interaction Mechanisms.

Cichorium glandulosum Boiss. et Huet (CGB) extract has an α-glucosidase inhibitory effect (IC50 = 59.34 ± 0.07 µg/mL, positive control drug acarbose IC50 = 126.1 ± 0.02 µg/mL), but the precise enzyme inhibitors implicated in this process are not known. The screening of α-glucosidase inhibitors in CGB extracts was conducted by bioaffinity ultrafiltration, and six potential inhibitors (quercetin, lactucin, 3-O-methylquercetin, hyperoside, lactucopicrin, and isochlorogenic acid B) were screened as the precise inhibitors. The binding rate calculations and evaluation of enzyme inhibitory effects showed that lactucin and lactucopicrin exhibited the greatest inhibitory activities. Next, the inhibiting effects of the active components of CGB, lactucin and lactucopicrin, on α-glucosidase and their mechanisms were investigated through α-glucosidase activity assay, enzyme kinetics, multispectral analysis, and molecular docking simulation. The findings demonstrated that lactucin (IC50 = 52.76 ± 0.21 µM) and lactucopicrin (IC50 = 17.71 ± 0.64 µM) exhibited more inhibitory effects on α-glucosidase in comparison to acarbose (positive drug, IC50 = 195.2 ± 0.30 µM). Enzyme kinetic research revealed that lactucin inhibits α-glucosidase through a noncompetitive inhibition mechanism, while lactucopicrin inhibits it through a competitive inhibition mechanism. The fluorescence results suggested that lactucin and lactucopicrin effectively reduce the fluorescence of α-glucosidase by creating lactucin-α-glucosidase and lactucopicrin-α-glucosidase complexes through static quenching. Furthermore, the circular dichroism (CD) and Fourier transform infrared spectroscopy (FT-IR) analyses revealed that the interaction between lactucin or lactucopicrin and α-glucosidase resulted in a modification of the α-glucosidase's conformation. The findings from molecular docking and molecular dynamics simulations offer further confirmation that lactucopicrin has a robust binding affinity for certain residues located within the active cavity of α-glucosidase. Furthermore, it has a greater affinity for α-glucosidase compared to lactucin. The results validate the suppressive impact of lactucin and lactucopicrin on α-glucosidase and elucidate their underlying processes. Additionally, they serve as a foundation for the structural alteration of sesquiterpene derived from CGB, with the intention of using it for the management of diabetic mellitus.

Cichorium glandulosum Ameliorates HFD-Induced Obesity in Mice by Modulating Gut Microbiota and Bile Acids.

Obesity is an ongoing global health problem, and Cichorium glandulosum (CG, chicory) is traditionally used as a hepatoprotective and lipid-lowering drug. However, there is still a lack of research on the role of CG in the treatment of obesity. In the present study, we found that CG significantly delayed weight gain and positively affected glucolipid metabolism disorders, serum metabolism levels, and the degree of liver and kidney oxidative stress in high-fat diet (HFD) mice. Further examination of the effects of CG on intestinal microenvironmental dysregulation and its metabolites in HFD mice revealed that the CG ethanol extract high-dose group (CGH) did not have a significant regulatory effect on short-chain fatty acids. Still, CGH significantly decreased the levels of 12α-OH/non-12α-OH bile acids and also found significant upregulation of proteobacteria and downregulation of cyanobacteria at the phylum level. CG may have ameliorated obesity and metabolic abnormalities in mice by repairing gut microbiota dysbiosis and modulating bile acid biosynthesis.

α5-nAChR/ADAM10 signaling mediates nicotine-related cutaneous melanoma progression via STAT3 activation.

Skin cutaneous melanoma (SKCM) is the skin malignancy with the highest mortality rate, and its morbidity rate is on the rise worldwide. Smoking is an independent marker of poor prognosis in melanoma. The α5-nicotinic acetylcholine receptor (α5-nAChR), one of the receptors for nicotine, is involved in the proliferation, migration and invasion of SKCM cells. Nicotine has been reported to promote the expression of a disintegrin and metalloproteinase 10 (ADAM10), which is the key gene involved in melanoma progression. Here, we explored the link between α5-nAChR and ADAM10 in nicotine-associated cutaneous melanoma. α5-nAChR expression was correlated with ADAM10 expression and lower survival in SKCM. α5-nAChR mediated nicotine-induced ADAM10 expression via STAT3. The α5-nAChR/ADAM10 signaling axis was involved in the stemness and migration of SKCM cells. Furthermore, α5-nAChR expression was associated with ADAM10 expression, EMT marker expression and stemness marker expression in nicotine-related mice homograft tissues. These results suggest the role of the α5-nAChR/ADAM10 signaling pathway in nicotine-induced melanoma progression.

Postoperative pain relief after total knee arthroplasty: A Bayesian network meta-analysis and systematic review of analgesic strategies based on nerve blocks.

STUDY OBJECTIVE: A Bayesian network meta-analysis was performed to compare the analgesic efficacy of the following nerve block techniques: femoral nerve block (FNB), adductor canal block (ACB), infiltration between the popliteal artery and the capsule of the posterior knee (iPACK), and genicular nerve block (GNB) following total knee arthroplasty (TKA). DESIGN: Systematic review and network meta-analysis (NMA). PATIENTS AND MEASUREMENTS: We searched the Web of Science, PubMed, EMBASE, and Cochrane Library databases until September 20, 2022. Patients who were treated by any of the above four nerve block techniques (alone or in combination) after TKA were included. Patients who underwent minimally invasive knee surgery were excluded. The indicators included pain scores during rest and mobilization, opioid consumption after surgery, postsurgical mobilization function (ROM [range of motion], TUG [Timed-Up-and-Go] test) at 24 h and 48 h, and length of hospital stay. The risk of bias was assessed by the Cochrane risk of bias tool. RESULTS: Forty-two studies involving 2857 patients were eligible for this study. This NMA suggested that ACB + iPACK was the most efficacious option for improving ambulation ability and shortening the length of hospital stay. Furthermore, ACB + iPACK was the best regimen for resting-pain and movement-pain relief (78% and 87%, respectively) and for reducing opioid consumption (90%) at 48 h. However, FNB + iPACK was the most efficacious option for relief of resting pain (42%) and reducing opioid consumption (68%) at 24 h; GNB was the most efficacious option for movement pain relief at 24 h (94%). CONCLUSION: Considering both pain control and knee functional recovery, ACB + iPACK may be the optimal analgesic regimen for patients after TKA. At the same time, it significantly reduces pain and opioid consumption at 48 h. However, ACB + iPACK is not the recommended technique for short-term (24 h) pain control. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42022362322).

Nomograms for Predicting Risk and Survival of Esophageal Cancer Lung Metastases: a SEER Analysis.

Background: The overall survival rate is notably low for esophageal cancer patients with lung metastases (LM), presenting significant challenges in their treatment. Methods: Through the Surveillance, Epidemiology, and End Results (SEER) program, individuals diagnosed with esophageal cancer between 2010 and 2015 were enrolled. Based on whether esophageal cancer metastasized to the lungs, we used propensity score matching (PSM) to balance correlated variables. Propensity score matching was a critical step in our study that helped to minimize the impact of possible confounders on the study results. We balanced variables related to lung metastases using the PSM method to ensure more accurate comparisons between the study and control groups. Specifically, we performed PSM in the following steps. First, we performed a univariate logistic regression analysis to screen for variables associated with lung metastasis. For each patient, we calculated their propensity scores using a logistic regression model, taking into account several factors, including gender, T-stage, N-stage, surgical history, radiotherapy history, chemotherapy history, and bone/brain/liver metastases. We used a 1:1 matching ratio based on the propensity score to ensure more balanced baseline characteristics between the study and control groups after matching. After matching, we validated the balance of baseline characteristics to ensure that the effect of confounders was minimized. We used logistic regression to identify risk variables for LM, while Cox regression was used to find independent prognostic factors. We then created nomograms and assessed their accuracy using the calibration curve, receiver operating curves (ROC), and C index. Results: In the post-PSM cohort, individuals diagnosed with LM experienced a median overall survival (OS) of 5.0 months (95% confidence interval [CI] 4.3-5.7), which was significantly lower than those without LM (P<0.001). LM has been associated to sex, T stage, N stage, surgery, radiation, chemotherapy, and bone/brain/liver metastases. LM survival was affected by radiation, chemotherapy, and bone/liver metastases. The nomograms' predictive power was proved using the ROC curve, C-index, and validation curve. Conclusion: Patients with LM have a worse chance of surviving esophageal cancer. The nomograms can effectively predict the risk and prognosis of lung metastases from esophageal cancer.

Integrated identification-quantification (ID-Quant) workflow utilizing UPLC-QTOF-MS for the therapeutic drug monitoring of multi-component antibiotics without pure standards: Validation using teicoplanin.

The lack of individual pure standard has hampered the application of therapeutic drug monitoring (TDM) for multi-component antibiotics in clinical laboratories. Here, we aimed to develop an integrated identification-quantification (ID-Quant) workflow based on ultra-high-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS) to enable the comprehensive determination of all teicoplanin components without needing pure standards. The workflow comprises three steps. First, non-targeted MSE full scanning was used to detect and identify all potential ingredients. Then, characteristic product ions were selected to generate a quantitative time-of-flight multiple reaction monitoring (Tof-MRM) method. Finally, the constituent composition of teicoplanin injection was determined and utilized as an alternative reference standard to monitor the teicoplanin ingredients in human serum samples. As a result, nine teicoplanin analogs were identified from teicoplanin injection (Sanofi-Aventis, France). The overall performance of the Tof-MRM method was satisfactory in terms of linearity, precision, accuracy, and limits of detection. Utilizing the drug as standard, the individual concentrations for each component in patient serum were determined to be 0.120 µg/mL (A3-1), 0.020 µg/mL (N-1), 0.550 µg/mL (N-2), 0.730 µg/mL (A2-1), 4.26 µg/mL (A2-2,3), 4.79 µg/mL (A2-4,5), and 0.290 µg/mL (N-3), respectively. The distribution pattern of teicoplanin components was also discovered to differ from that in the drug injection. Overall, this integrated ID-Quant workflow based on UHPLC-QTOF-MS enables the robust quantitation of all teicoplanin analogs without the need for individual pure standard. This approach could help address the standard unavailability problem in the TDM of multi-component antibiotics.

miR-214-PTEN pathway is a potential mechanism for stress-induced immunosuppression affecting chicken immune response to avian influenza virus vaccine.

Stress-induced immunosuppression (SIIS) is one of common problems in the intensive poultry industry, affecting the effect of vaccine immunization and leading to high incidences of diseases. In this study, the expression characteristics and regulatory mechanisms of miR-214 in the processes of SIIS and its influence on the immune response to avian influenza virus (AIV) vaccine in chicken were explored. The qRT-PCR results showed that serum circulating miR-214 was significantly differentially expressed (especially on 2, 5, and 28 days post immunization (dpi)) in the processes, so had the potential as a molecular marker. MiR-214 expressions from multiple tissues were closely associated with the changes in circulating miR-214 expression levels. MiR-214-PTEN regulatory network was a potential key regulatory mechanism for the heart, bursa of Fabricius, and glandular stomach to participate in the process of SIIS affecting AIV immune response. This study can provide references for further understanding of stress affecting immune response.

Tunable Photocarrier Dynamics in CuS Nanoflakes under Pressure Modulation.

Two-dimensional materials with a unique layered structure have attracted intense attention all around the world due to their extraordinary physical properties. Most importantly, the internal Coulomb coupling can be regulated, and thus electronic transition can be realized by manipulating the interlayer interaction effectively through adding external fields. At present, the properties of two-dimensional materials can be tuned through a variety of methods, such as adding pressure, strain, and electromagnetic fields. For optoelectronic applications, the lifetime of the photogenerated carriers is one of the most crucial parameters for the materials. Here, we demonstrate effective modulation of the optical band gap structure and photocarrier dynamics in CuS nanoflakes by applying hydrostatic pressure via a diamond anvil cell. The peak differential reflection signal shows a linear blueshift with the pressure, suggesting effective tuning of interlayer interaction inside CuS by pressure engineering. The results of transient absorption show that the photocarrier lifetime decreases significantly with pressure, suggesting that the dissociation process of the photogenerated carriers accelerates. It could be contributed to the phase transition or the decrease of the phonon vibration frequency caused by the pressure. Further, Raman spectra reveal the change of Cu-S and S-S bonds after adding pressure, indicating the possible occurrence of structural phase transition. Interestingly, all of the variation modes are reversible after releasing pressure. This work has provided an excellent sight to show the regulation of pressure on the photoelectric properties of CuS, exploring CuS to wider applications that can lead toward the realization of future excitonic and photoelectric devices modulated by high pressure.

PKP2 induced by YAP/TEAD4 promotes malignant progression of gastric cancer.

Gastric cancer (GC) exhibits significant heterogeneity and its prognosis remains dismal. Therefore, it is essential to investigate new approaches for diagnosing and treating GC. Desmosome proteins are crucial for the advancement and growth of cancer. Plakophilin-2 (PKP2), a member of the desmosome protein family, frequently exhibits aberrant expression and is strongly associated with many tumor types' progression. In this study, we found upregulation of PKP2 in GC. Further correlation analysis showed a notable association between increased PKP2 expression and both tumor stage and poor prognosis in individuals diagnosed with gastric adenocarcinoma. In addition, our research revealed that the Yes-associated protein1 (YAP1)/TEAD4 complex could stimulate the transcriptional expression of PKP2 in GC. Elevated PKP2 levels facilitate activation of the AKT/mammalian target of rapamycin signaling pathway, thereby promoting the malignant progression of GC. By constructing a mouse model, we ultimately validated the molecular mechanism and function of PKP2 in GC. Taken together, these discoveries suggest that PKP2, as a direct gene target of YAP/TEAD4 regulation, has the potential to be used as an indication of GC progression and prognosis. PKP2 is expected to be a promising therapeutic target for GC.

Applications of tandem mass spectrometry (MS/MS) in antimicrobial peptides field: Current state and new applications.

Antimicrobial peptides (AMPs) constitute a group of small molecular peptides that exhibit a wide range of antimicrobial activity. These peptides are abundantly present in the innate immune system of various organisms. Given the rise of multidrug-resistant bacteria, microbiological studies have identified AMPs as potential natural antibiotics. In the context of antimicrobial resistance across various human pathogens, AMPs hold considerable promise for clinical applications. However, numerous challenges exist in the detection of AMPs, particularly by immunological and molecular biological methods, especially when studying of newly discovered AMPs in proteomics. This review outlines the current status of AMPs research and the strategies employed in their development, considering resent discoveries and methodologies. Subsequently, we focus on the advanced techniques of mass spectrometry for the quantification of AMPs in diverse samples, and analyzes their application, advantages, and limitations. Additionally, we propose suggestions for the future development of tandem mass spectrometry for the detection of AMPs.

Plasma Steroid Profiling Combined With Machine Learning for the Differential Diagnosis in Mild Autonomous Cortisol Secretion From Nonfunctioning Adenoma in Patients With Adrenal Incidentalomas.

OBJECTIVE: To assess the diagnostic value of combining plasma steroid profiling with machine learning (ML) in differentiating between mild autonomous cortisol secretion (MACS) and nonfunctioning adenoma (NFA) in patients with adrenal incidentalomas. METHODS: The plasma steroid profiles data in the laboratory information system were screened from January 2021 to December 2023. EXtreme Gradient Boosting was applied to establish diagnostic models using plasma 24-steroid panels and/or clinical characteristics of the subjects. The SHapley Additive exPlanation (SHAP) method was used for explaining the model. RESULTS: Seventy-six patients with MACS and 86 patients with NFA were included in the development and internal validation cohort while the external validation cohort consisted of 27 MACS and 21 NFA cases. Among 5 ML models evaluated, eXtreme Gradient Boosting demonstrated superior performance with an area under the curve of 0.77 using 24 steroid hormones. The SHAP method identified 5 steroids that exhibited optimal performance in distinguishing MACS from NFA, namely dehydroepiandrosterone, 11-deoxycortisol, 11ß-hydroxytestosterone, testosterone, and dehydroepiandrosteronesulfate. Upon incorporating clinical features into the model, the area under the curve increased to 0.88, with a sensitivity of 0.77 and specificity of 0.82. Furthermore, the results obtained through SHAP revealed that lower levels of testosterone, dehydroepiandrosterone, low-density lipoprotein cholesterol, body mass index, and adrenocorticotropic hormone along with higher level of 11-deoxycortisol significantly contributed to the identification of MACS in the model. CONCLUSIONS: We have elucidated the utilization of ML-based steroid profiling to discriminate between MACS and NFA in patients with adrenal incidentalomas. This approach holds promise for distinguishing these 2 entities through a single blood collection.

Targeted ferritinophagy in gastrointestinal cancer: from molecular mechanisms to implications.

Gastrointestinal cancer is a significant global health burden, necessitating the development of novel therapeutic strategies. Emerging evidence has highlighted the potential of targeting ferritinophagy as a promising approach for the treatment of gastrointestinal cancer. Ferritinophagy is a form of selective autophagy that is mediated by the nuclear receptor coactivator 4 (NCOA4). This process plays a crucial role in regulating cellular iron homeostasis and has been implicated in various pathological conditions, including cancer. This review discusses the molecular mechanisms underlying ferritinophagy and its relevance to gastrointestinal cancer. Furthermore, we highlight the potential therapeutic implications of targeting ferritinophagy in gastrointestinal cancer. Several approaches have been proposed to modulate ferritinophagy, including small molecule inhibitors and immunotherapeutic strategies. We discuss the advantages and challenges associated with these therapeutic interventions and provide insights into their potential clinical applications.

Positive GLI1/INHBA feedback loop drives tumor progression in gastric cancer.

GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.