Targeting LINC00665/miR-199b-5p/SERPINE1 axis to inhibit trastuzumab resistance and tumorigenesis of gastric cancer via PI3K/AKt pathway.

Long noncoding RNAs (lncRNAs) serve as critical mediators of tumor progression and drug resistance in cancer. Herein, we identified a lncRNA, LINC00665, associated with trastuzumab resistance and development in gastric cancer (GC). LINC00665 was highly expressed in GC tissues and high expression of LINC00665 was correlated with poor prognosis. LINC00665 knockdown was verified to suppress migration, invasion, and resistance to trastuzumab in GC. Furthermore, we found that LINC00665 participates in the infiltration of naive B cells, mast cells, and T follicular helper (Tfh) cells. Mechanistically, LINC00665 was confirmed to regulate tumorigenesis and trastuzumab resistance by activating PI3K/AKt pathway. LINC00665 sponged miR-199b-5p to interact with SERPINE1 expression, resulting in the increase of phosphorylation of AKt, thus participating in the PI3K/AKt pathway. To summarize, LINC00665 facilitated the tumorigenesis and trastuzumab resistance of GC by sponging miR-199b-5p and promoting SERPINE1 expression, which further activated PI3K/AKt signaling; this finding reveals a new mechanism by which LINC00665 modulates tumor development and drug resistance in GC.

Exploring near-infrared autofluorescence properties in parathyroid tissue: an analysis of fresh and paraffin-embedded thyroidectomy specimens.

Significance: Near-infrared autofluorescence (NIRAF) utilizes the natural autofluorescence of parathyroid glands (PGs) to improve their identification during thyroid surgeries, reducing the risk of inadvertent removal and subsequent complications such as hypoparathyroidism. This study evaluates NIRAF's effectiveness in real-world surgical settings, highlighting its potential to enhance surgical outcomes and patient safety. Aim: We evaluate the effectiveness of NIRAF in detecting PGs during thyroidectomy and central neck dissection and investigate autofluorescence characteristics in both fresh and paraffin-embedded tissues. Approach: We included 101 patients diagnosed with papillary thyroid cancer who underwent surgeries in 2022 and 2023. We assessed NIRAF's ability to locate PGs, confirmed via parathyroid hormone assays, and involved both junior and senior surgeons. We measured the accuracy, speed, and agreement levels of each method and analyzed autofluorescence persistence and variation over 10 years, alongside the expression of calcium-sensing receptor (CaSR) and vitamin D. Results: NIRAF demonstrated a sensitivity of 89.5% and a negative predictive value of 89.1%. However, its specificity and positive predictive value (PPV) were 61.2% and 62.3%, respectively, which are considered lower. The kappa statistic indicated moderate to substantial agreement (kappa = 0.478; P < 0.001 ). Senior surgeons achieved high specificity (86.2%) and PPV (85.3%), with substantial agreement (kappa = 0.847; P < 0.001 ). In contrast, junior surgeons displayed the lowest kappa statistic among the groups, indicating minimal agreement (kappa = 0.381; P < 0.001 ). Common errors in NIRAF included interference from brown fat and eschar. In addition, paraffin-embedded samples retained stable autofluorescence over 10 years, showing no significant correlation with CaSR and vitamin D levels. Conclusions: NIRAF is useful for PG identification in thyroid and neck surgeries, enhancing efficiency and reducing inadvertent PG removals. The stability of autofluorescence in paraffin samples suggests its long-term viability, with false positives providing insights for further improvements in NIRAF technology.

Characteristics of Nocturnal Boundary Layer over a Subtropical Forest: Implications for the Dispersion and Fate of Atmospheric Species.

The nocturnal boundary layer (NBL) significantly influences the dispersion and fate of atmospheric species at night. Subtropical forests are crucial in carbon and water exchange between the biosphere and the atmosphere. However, the NBL characteristics and their impact on atmospheric species over these forests remain unknown. This study conducted vertical measurements of atmospheric species such as O3 and volatile organic compounds (VOCs), along with meteorological variables, over a national forest reserve in Southern China. Results reveal that the NBL height ranged from 180 to 300 m in the summer and from 80 to 160 m in the winter. The vertical distribution of chemical species varied by time and season, with greater concentration gradients observed in the summer. Over 90% of VOCs above the NBL were anthropogenic, while biogenic VOCs were mainly found within the NBL. Higher O3 concentration and VOC product-to-reactant ratios were observed in the residual layer, suggesting enhanced oxidation levels. This unique vertical distribution of atmospheric species at night is driven by factors, such as emission, deposition, turbulence, and atmospheric chemistry, potentially affecting ecosystem functions. Results from this study highlight the importance of incorporating NBL dynamics into atmospheric models to better understand the evolution of chemical species and their ecological effects over forests.

Early prediction of acute pancreatitis with acute kidney injury using abdominal contrast-enhanced CT features.

Early prediction of acute pancreatitis (AP) with acute kidney injury (AKI) using abdominal contrast-enhanced CT could effectively reduce the mortality and the economic burden on patients and society. However, this challenge is limited by the imaging manifestations of early-stage AP that are not clearly visible to the naked eye. To address this, we developed a machine learning model using imperceptible variations in the structural changes of pancreas and peripancreatic region, extracted by radiomics and artificial intelligence technology, to screen and stratify the high-risk AP patients at the early stage of AP. The results demonstrate that the machine learning model could screen the high-risk AP with AKI patients with an area under the curve (AUC) of 0.82 for the external cohort, superior to the human radiologists. This finding confirms the significant potential of machine learning in the screening of acute pancreatitis and contributes to personalized treatment and management for AP patients.

Brain-targeted ursolic acid nanoparticles for anti-ferroptosis therapy in subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy. METHODS: SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis. RESULTS: We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway. CONCLUSIONS: Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal.

Combined detection of hepatitis B virus surface antigen and hepatitis B virus DNA using a DNA sensor.

Hepatitis B virus (HBV) infection is associated with the progression of liver disease. Occult HBV infection (OBI) is defined as the existence of detectable HBV DNA in HBV surface antigen negative individuals. However, HBV DNA is negative in serum while HBV surface antigen remains positive in incompletely cured chronic HBV infection. Hence, combined detection of HBV surface antigen and HBV DNA is essential for the accurate detection and rehabilitation of HBV infection. Therefore, a multiplex detection strategy based on branched DNA nanostructures was developed. The single-stranded segment of a branched DNA nanostructure (segments of S4 and S2) assembled by four single-stranded DNA was hybridized with the aptamer of HBV surface antigen and DNA hairpin to construct a DNA nanosensor, which can achieve high specificity identification and highly sensitive fluorescence responses to the targets. The detection limits of the developed nanosensor for HBV and HBV DNA are 50 pM and 5 nM, respectively. The combined detection of HBV surface antigen and HBV DNA provides a new insight for more thorough diagnostic evaluation of HBV infection and rehabilitation.

MRI-based microplastic tracking in vivo and targeted toxicity analysis.

Microplastics (MPs) as an emerging pollutant have raised significant concerns in environmental health. However, elucidating the distribution of MPs in living organisms remains challenging due to their trace residue and tough detection problems. In this study, a novel magnetic resonance imaging (MRI)-based tracking method was employed to monitor functionalized MPs biodistribution in vivo. Our results identified that the liver is the primary accumulation site of polystyrene microplastics (PS-MPs) in biological systems through continuous in vivo monitoring spanning 21 days. Biochemical tests were performed to assess the toxicological effects of functionalized MPs on the liver tissue, revealing hepatocyte death, inflammatory cell infiltration, and alterations in alkaline phosphatase levels. Notably, positively charged MPs exhibited more severe effects. A combined metabolomics-proteomics analysis further revealed that PS-MPs interfered with hepatic metabolic pathways, particularly bile secretion and ABC transporters. Overall, this study effectively assessed the distribution of functionalized MPs in vivo utilizing MRI technology, validated toxicity in targeted organ, and conducted an in-depth study on underlying biotoxicity mechanism. These findings offer crucial scientific insights into the potential impact of MPs in the actual environment on human health.

Molecular mechanism of Dang-Shen-Yu-Xing decoction against Mycoplasma bovis pneumonia based on network pharmacology, molecular docking, molecular dynamics simulations and experimental verification.

Mycoplasma bovis pneumonia is a highly contagious respiratory infection caused by Mycoplasma bovis. It is particularly prevalent in calves, posing a significant threat to animal health and leading to substantial economic losses. Dang-Shen-Yu-Xing decoction is often used to treat this condition in veterinary clinics. It exhibits robust anti-inflammatory effects and can alleviate pulmonary fibrosis. However, its mechanism of action remains unclear. Therefore, this study aimed to preliminarily explore the molecular mechanism of Dang-Shen-Yu-Xing decoction for treating mycoplasma pneumonia in calves through a combination of network pharmacology, molecular docking, molecular dynamics simulation methods, and experimental validation. The active components and related targets of Dang-Shen-Yu-Xing decoction were extracted from several public databases. Additionally, complex interactions between drugs and targets were explored through network topology, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Subsequently, the binding affinity of drug to disease-related targets was verified through molecular docking and molecular dynamics simulation. Finally, the pharmacodynamics were verified via animal experiments. The primary network topology analysis revealed two core targets and 10 key active components of Dang-Shen-Yu-Xing decoction against Mycoplasma bovis pneumonia. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that the mechanism of Dang-Shen-Yu-Xing decoction for treating mycoplasma bovis pneumonia involved multiple signaling pathways, with the main pathways including PI3K-Akt and IL17 signaling pathways. Moreover, molecular docking predicted the binding affinity and conformation of the core targets of Dang-Shen-Yu-Xing decoction, IL6, and IL10, with the associated main active ingredients. The results showed a strong binding of the active ingredients to the hub target. Further, molecular docking dynamics simulation revealed three key active components of IL10 induced by Dang-Shen-Yu-Xing decoction against Mycoplasma bovis pneumonia. Finally, animal experiments confirmed Dang-Shen-Yu-Xing decoction pharmacodynamics, suggesting that it holds potential as an alternative therapy for treating mycoplasma bovis pneumonia.

An Oriented Diffusion Strategy to Configure All-Region Ultrahigh-Density Metal Single Atoms for High-Capacity Sodium Storage.

Single-atom metals (SAMs), despite being promising for high-utilization catalysis, biomedicine, and energy storage, usually suffer from limited catalytic performance caused by low metal loading. Herein, via an oriented diffusion strategy, all-region ultrahigh-loading (18.9 wt.%) Sn-SAMs over carbon nanorings matrix (Sn-SAMs@CNR) are initially achieved based on the transformation of a g-C3N4@SnO2@polydopamine ring-like nested structure. The formation process of Sn-SAMs involves a critical conversion from oxygen-coordination (SnO2) to nitrogen-coordination (Sn-N4) and simultaneous anti-Osterwalder ripening promoted under spatial confinement. Notably, the g-C3N4-derived N-containing gaseous intermediates dynamically drive the oriented diffusion (inside-out diffusion) of Sn-SAMs across the carbon nanorings, realizing an all-region ultrahigh loading of SAMs throughout the carbon matrix. This strategy is also applied to other metal materials (Fe, Co, Ni, Cu, and Sb), and features excellent universality. When applied as the anode for sodium-ion batteries, experimental analyses and theoretical calculations demonstrate that high-loading Sn-N4 active sites significantly optimize electron density distribution and improve reaction kinetics. Consequently, Sn-SAMs@CNR exhibits outstanding durability of 364 mAh g-1   even after 5000 cycles with an impressively low (0.00068%) capacity decay per cycle. This work opens up a universally new avenue for all-region ultrahigh loading of SAMs to carbon matrix for high-performance energy storage.

Pharmacophylogenetic insights into Scutellaria strigillosa Hemsl.: chloroplast genome and untargeted metabolomics, quantitative analysis and antibacterial analysis.

Scutellaria strigillosa Hemsl., known for its traditional use in Chinese herbal medicine, is valued for heat-clearing and detoxifying, promoting diuresis, reducing swelling, alleviating pain, and preventing miscarriage. Despite its historical use, comprehensive studies on pharmacophylogenetic analysis, including genetic and chemical profiles and the antimicrobial activity of S. strigillosa are still lacking. Understanding these aspects is crucial for fully realizing its therapeutic potential and ensuring sustainable use. This study aims to elucidate these aspects through comparative genomics, metabolomics, and antimicrobial assays with Scutellaria baicalensis Georgi and Scutellaria barbata D. Don. The chloroplast genome of S. strigillosa was assembled, measuring 152,533 bp, and revealing a high degree of conservation, especially in the protein-coding regions, and identified four regions trnK(UUU)-rps16, trnN(GUU)-trnR(ACG), accD-psaI, psbE-petL) of variability that could serve as phylogenetic markers. The phylogenetic analysis revealed a closer genetic relationship of S. strigillosa with S. tuberifera and S. scordifolia than traditionally classified, suggesting a need for taxonomic reevaluation within the genus. UPLC-Q-TOF-MS analysis in negative ion mode was used to explore the chemical diversity among these species, revealing distinct variations in their chemical compositions. S. strigillosa shared a closer chemical profile with S. barbata, aligning with phylogenetic findings. Metabolomic identification through Progenesis QI software resulted in the tentative identification of 112 metabolites, including a substantial number of flavonoids, diterpenoids, iridoid glycosides, phenylethanoid glycosides, and others. HPLC analysis further detailed the concentrations of 12 actives across the species, highlighting the variation in compound content. S. strigillosa shows antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, similar to S. baicalensis root extracts. This research enhances the understanding of the phylogenetic and phytochemical profiles and the antibacterial activity of S. strigillosa, offering new insights into its medicinal properties. The findings suggest a need for taxonomic reevaluation within the genus and underscore the potential antibacterial activity of S. strigillosa for therapeutic applications. Further studies are encouraged to explore its full medicinal potential and contribute to the sustainable development of Scutellaria species.

A droplet digital PCR method for the detection of scale drop disease virus in yellowfin seabream (Acanthopagrus latus).

In this study, a ddPCR method for the detection of scale drop disease virus (SDDV) in yellowfin seabream (Acanthopagrus latus) was established based on Real-time fluorescence quantitative PCR detection methods and principles. The reaction conditions were optimized, and the sensitivity, specificity, accuracy, and reproducibility were assessed. The results showed that threshold line position was determined to be 1900 by the ddPCR method; the optimum annealing temperature for SDDV detection by the ddPCR method was 60°C; the limit of detection was 1.4-1.7 copies/µL; the results of specific detection of other common viruses, except for SDDV specific amplification, were all negative; and the relative standard deviation (RSD) for the reproducibility validation was 0.77%. The samples of yellowfin seabream (Acanthopagrus latus) liver, spleen, kidney, heart, intestine, brain, blood, muscle, skin and ascites with three replicates, respectively, were tested using the ddPCR method, and the results were consistent with clinical findings. The ddPCR method established in this study has the advantages of high sensitivity, high specificity, good reproducibility and simple steps for the quantitative detection of SDDV, which could be used for the nucleic acid detection of clinical SDDV samples, and provided a new quantitative method for the diagnosis of yellowfin seabream SDDV in the early stage of pathogenesis.

Effects of fibrolytic and amylolytic compound enzyme preparation on rumen fermentation, serum parameters and production performance in primiparous early-lactation dairy cows.

This research communication reports the effects of a compound enzyme preparation consisting of fibrolytic (cellulase 3500 CU/g, xylanase 2000 XU/g, ß-glucanase 17 500 GU/g) and amylolytic (amylase 37 000 AU/g) enzymes on nutrient intake, rumen fermentation, serum parameters and production performance in primiparous early-lactation (47 ± 2 d) dairy cows. Twenty Holstein-Friesian cows in similar body condition scores were randomly divided into control (CON, n = 10) and experimental (EXP, n = 10) groups in a completely randomized single-factor design. CON was fed a basal total mixed ration diet and EXP was dietary supplemented with compound enzyme preparation at 70 g/cow/d. The experiment lasted 4 weeks, with 3 weeks for adaptation and then 1 week for measurement. Enzyme supplementation significantly increased diet non-fibrous carbohydrates (NFC) content as well as dry matter intake (DMI) and NFC intake (P < 0.05). EXP had increased ruminal butyrate and isobutyrate percentages (P < 0.01) but decreased propionate and valerate percentages (P < 0.05), as well as increased serum alkaline phosphatase activity and albumin concentration (P ≤ 0.01). Additionally, EXP had increased milk yield (0.97 kg/d), 4% fat corrected milk yield and energy corrected milk yield, as well as milk fat and protein yield (P < 0.01). In conclusion, dietary supplementation with a fibrolytic and amylolytic compound enzyme preparation increased diet NFC content, DMI and NFC intake, affected rumen fermentation by increasing butyrate proportion at the expense of propionate, and enhanced milk performance in primiparous early-lactation dairy cows.

Soil temperature and fungal diversity jointly modulate soil heterotrophic respiration under short-term warming in the Zoige alpine peatland.

Global warming has changed carbon cycling in terrestrial ecosystems, but it remains unclear how climate warming affects soil heterotrophic respiration (Rh). We conducted a field experiment in the Zoige alpine peatland to investigate the mechanism of how short-term warming affects Rh by examining the relationships between plant biomass, soil properties, soil microbial diversity, and functional groups and Rh. Our results showed that warming increased Rh after one growing season of warming. However, warming barely changed the bacterial functional groups involved in the carbon cycle predicted by the functional annotation analysis. According to the Mantel test, NO3- was found to be the primary determinant for bacterial and fungal communities. The results of the Structural Equation Model (SEM) indicate that soil temperature and fungal diversity jointly modulate Rh, suggesting that short-term warming may not affect Rh by altering the structural and functional composition of microorganisms, which provides new insight into the mechanisms of the effects of warming on Rh in terrestrial ecosystems.

Ferroptosis in eye diseases: a systematic review.

Ferroptosis is a type of iron-dependent cell death that differs from apoptosis, necroptosis, autophagy, and other forms of cell death. It is mainly characterized by the accumulation of intracellular lipid peroxides, redox imbalance, and reduced levels of glutathione and glutathione peroxidase 4. Studies have demonstrated that ferroptosis plays an important regulatory role in the occurrence and development of neurodegenerative diseases, stroke, traumatic brain injury, and ischemia-reperfusion injuries. Multiple mechanisms, such as iron metabolism, ferritinophagy, p53, and p62/Keap1/Nrf2, as well as the combination of FSP1/CoQ/NADPH and hepcidin/FPN-1 can alter the vulnerability to ferroptosis. Nevertheless, there has been limited research on the development and management of ferroptosis in the realm of eye disorders, with most studies focusing on retinal conditions such as age-related macular degeneration and retinitis pigmentosa. This review offers a thorough examination of the disruption of iron homeostasis in eye disorders, investigating the underlying mechanisms. We anticipate that the occurrence of ferroptotic cell death will not only establish a fresh field of study in eye diseases, but also present a promising therapeutic target for treating these diseases.

Lensless super-resolved quantitative phase imaging with cm-level lateral translations of two glass plates.

In this Letter, we propose a new, to the best of our knowledge, lensless on-chip holographic microscopy platform, which can acquire sub-pixel-shifting holograms through centimeter (cm)-level lateral translations. An LED light source is used to illuminate the sample, and two orthogonally tilted step-structure glass plates are inserted into the optical path. By merely displacing the glass plates under cm-level precision, a series of holograms with sub-pixel displacements can be obtained. Combined with our improved pixel super-resolution (PSR) algorithm, high-quality PSR phase imaging can be achieved. Tests on the high-resolution USAF1951 target demonstrate that the system can achieve a half-width resolution of 870 nm by a camera with a pixel size of 1.67 µm. Additionally, imaging experiments were conducted on phase-type sinusoidal gratings, yeasts, red blood cells, and lilium ovary sections, respectively. The results show that the system can achieve large field-of-view, high-resolution phase imaging under low-cost hardware conditions and holds promise for its applications in biology and medicine.

Maternal e-cigarette exposure alters DNA methylome, site-specific CpG and CH methylation, and transcriptomic signatures in the neonatal brain.

Maternal use of e-cigarette (e-cig) aerosols poses significant risks to fetal brain development, potentially increasing susceptibility to neurodevelopmental disorders in later life. However, the underlying mechanisms remain incompletely understood. This study aimed to understand the effects of fetal e-cig exposure on DNA methylome and transcriptomic changes in the neonatal brain. Pregnant rats were exposed to e-cig aerosols, and neonatal brains (5 males and 5 females/group) from both control and e-cig-exposed groups were used for experimental analysis. Results indicated that prenatal e-cig exposure altered site-specific DNA methylation patterns at both CpG and CH (non-CpG) sites, predominantly in intergenic and intronic regions, with sex dimorphism in methylation and gene expression changes. Gene ontology analysis revealed that e-cig exposure not only affected neuron projection development and axonogenesis but also altered pathways related to neurodegeneration and long-term depression. These findings provide novel insights into the dynamic changes of CpG and CH methylation induced by e-cig exposure, underscoring the susceptibility of the developing brain to maternal e-cig exposure and its potential implications for developmental disorders and neurodegenerative diseases later in life.

Microstructure, Hardness and High-Temperature Corrosion Behaviors in Sulfur-Containing Environment of Laser Cladding Y2O3/IN625 Composite Coating.

Water-cooled wall tubes are susceptible to high-temperature corrosion during service. Applying high-performance coatings via laser cladding on the tube surfaces can significantly enhance corrosion resistance and extend the service life of the tubes, providing substantial economic advantages. This paper prepared Y2O3/IN625 composite coating by means of high-speed laser cladding. Furthermore, the effects of Y2O3 addition on the microstructure evolution, hardness, as well as the high-temperature corrosion behaviors have been systematically investigated. The results show that Y2O3 addition can effectively refine the microstructure of the Inconel 625 coating, but the phase composition has little change. The coating's hardness can also be improved by about 7.7%, reaching about 300 HV. Compared to Inconel 625 coating, the Y2O3-added composited coating shows superior high-temperature corrosion resistance, with the corrosion mass gain decreased by about 36.6%. The denser and tightly bonded Cr-rich oxides layer can be formed adjacent to the coating surface, which plays a predominant role in improving the coating corrosion resistance.

Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). With the aim of understanding and modulating neosubstrate specificity, we recently reported the discovery of SJ3149 (4), a selective and potent molecular glue degrader of CK1α, that is active in multiple cancer cell lines. Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.

SET facilitates immune escape of microsatellite stability colorectal cancer by inhibiting c-Myc degradation.

Microsatellite stability (MSS) colorectal cancer (CRC) exhibits a low mutation load and poor immunogenicity, contributing to immune escape of tumor cells and less benefit from immune checkpoint blockade (ICB) treatment. The mechanisms underlying immunotherapeutic resistance in MSS CRC remain to be elucidated. Here, we identified that nuclear proto-oncogene SET is significantly higher expressed in MSS CRC compared to microsatellite instability (MSI) CRC and facilitates immune escape of MSS CRC. Mechanistically, SET represses the expression of C-C motif chemokine ligand 5 (CCL5) and upregulates mismatch repair (MMR) proteins expression in a c-Myc-dependent manner, which inhibits infiltration and migration of CD8+ T cells to tumor tissues and results in low immunogenicity in MSS CRC. In addition, we found that SET impairs ubiquitination and proteasomal degradation of c-Myc by disrupting the interaction between E3 ligase FBXW7 and c-Myc. Moreover, SET inhibition enhances the response to immunotherapy in MSS CRC in vivo. Overall, this study reveals the critical roles and posttranslational regulatory mechanism of SET in immune escape and highlights the SET/c-Myc axis as a potential target for immunotherapy of MSS CRC that have implications for targeting a unique aspect of this disease.