Zeng Z, Cao X, Li C
… +21 more, He Y, Guo H, Cao X, Gong T, Sun J, Hu Y, Hu Z, Lai Y, Zhang D, Warner N, Uhlig HH, Li Q, Muise AM, Tan Y, Huang Y, Deng L, Deng L, Sun Z, Zhong M, Zhang X, Li D
Sci China Life Sci
· 2026 Jun · PMID 42400713
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Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs r...Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs remain limited. In this study, we observed a positive correlation between spleen tyrosine kinase (SYK) activity in immune cells and tumor progression in human cancers. Utilizing a mouse model with a gain-of-function SYK mutation, we demonstrated that SYK activation promotes tumorigenesis in carcinogen-induced and xenograft models across multiple cancer types, largely through MDSC-dependent mechanisms. Mechanistically, SYK activates the JAK-STAT-CXCR2 signaling axis, enhancing MDSC migration and suppressing antitumor T cell responses. Notably, pharmacological inhibition of SYK not only inhibited tumor growth but also enhanced the therapeutic effect of anti-PD-1 in mouse models and patient-derived tumor organoid models. Our findings highlight the immunoregulatory role of SYK in tumor progression and suggest that targeting SYK represents a promising strategy to remodel the tumor microenvironment and enhance the efficacy of checkpoint blockade immunotherapy.
Song Y, Mao C, Liu P
… +7 more, Yang G, Kang L, Li Z, Zhou W, Liu X, Yao S, Yang Y
Sci China Life Sci
· 2026 Jun · PMID 42400712
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Thermokarst lakes represent a critical source of atmospheric methane (CH), owing to large amounts of microbially generated CH in sediments. However, the structure and function of lake sediment microbiota, as well as thei...Thermokarst lakes represent a critical source of atmospheric methane (CH), owing to large amounts of microbially generated CH in sediments. However, the structure and function of lake sediment microbiota, as well as their roles in mediating CH production, remain poorly understood across broad geographic scales. Here, we combined high-throughput sequencing, a 224-d anaerobic incubation, and stable isotopic analyses to investigate sediment microbiota and CH production across 30 thermokarst lakes along a 1,100 km permafrost transect on the Tibetan Plateau. Our results revealed that lake characteristics (i.e., lake depth and salinity-alkalinity) shaped sediment microbial composition and function. Deeper lakes exhibited enriched methanogenic taxa and pathways. In contrast, shallower lakes with higher salinity-alkalinity were dominated by microbial consortia that suppress net CH production via methanotrophs consuming CH and sulfate reducers competing with acetoclastic and hydrogenotrophic methanogens. Accordingly, cumulative CH production decreased by one order of magnitude from deeper lakes (2.5 logCH-C µg/g) to shallow and alkaline lakes (1.3 logCH-C µg/g) or salinity-alkalinity lakes (1.1 logCH-C µg/g). This variation was modulated by both key microbial consortia and sediment organic carbon and nitrogen supply. Overall, these results disentangled how lake characteristics restructured microbial dynamics to alter sediment CH production, and identified critical microbial consortia that could predict spatial variations in sediment CH production across thermokarst lakes.
Qi Y, Chen Y, Guo H
… +13 more, Guo H, Hang R, Jia G, Li Y, Mo B, Wang Z, Wu L, Xia Y, Yang X, Zhai J, Zheng B, Zhu D, Cao X
Sci China Life Sci
· 2026 Jun · PMID 42387081
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Eukaryotic genomes are pervasively transcribed, producing a vast repertoire of RNA molecules. In plants, diverse RNA species play pivotal roles in regulating growth, development, and responses to environmental stimuli. T...Eukaryotic genomes are pervasively transcribed, producing a vast repertoire of RNA molecules. In plants, diverse RNA species play pivotal roles in regulating growth, development, and responses to environmental stimuli. The activities of RNAs are determined not only by their nucleotide sequences but are also shaped by multiple regulatory mechanisms, including processing, turnover, chemical modifications, and higher-order structure formation-each contributing critically to phenotypic outcomes. Over the past decade, technological advances, particularly in high-throughput sequencing and genome editing, have substantially deepened our understanding of RNA regulation; concurrently, research in this field has expanded from foundational studies in Arabidopsis to encompass a broad range of crop species. Building upon this expanded knowledge, this review provides a comprehensive overview of the regulation and functions of RNAs in plants. Specifically, we discuss the roles and molecular mechanisms of diverse RNA types, the roles of RNA structures and modifications in regulatory processes, and the translational application of RNA-based strategies for improving agronomic traits. Finally, we outline future research directions and offer perspectives on harnessing RNA regulation to advance crop improvement.
Hou H, Lyu H, Yang H
… +7 more, Wang Y, Zhang T, Yang J, Yousuf S, Luo H, Yao X, Liu YX
Sci China Life Sci
· 2026 Jun · PMID 42377893
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Postharvest surface microbiota plays a pivotal role in fruit spoilage and disease development, directly influencing shelf life and food safety. In this study, we systematically investigated the dynamic changes of peel-as...Postharvest surface microbiota plays a pivotal role in fruit spoilage and disease development, directly influencing shelf life and food safety. In this study, we systematically investigated the dynamic changes of peel-associated microbial communities in two litchi cultivars with distinct storability (Huaizhi and Nuomici), under both natural and fungicide (prochloraz) treatments over a 9 d storage period. Amplicon sequencing, time-series analysis, and a random forest model identified five key genera-Acetobacter, Methylobacterium, Sphingomonas, Gluconobacter, and Pantoea-strongly associated with storage time. Notably, culturable isolates from these genera exhibited significant antagonistic activity against the common postharvest fungal pathogens Peronophythora litchii and Colletotrichum gloeosporioides, with Gluconobacter sp. Lc45 demonstrating high-efficiency antagonism. Furthermore, a random forest model based on microbial biomarkers accurately predicted fruit freshness (R>0.9). This study highlights the ecological and biocontrol significance of surface microbiota on litchi, and proposes microbial-based strategies as promising eco-friendly alternatives for postharvest disease control and freshness prediction in subtropical fruits.
AIMS: The molecular mechanisms that regulate Per3 expression in the pineal gland remain incompletely understood. This study aimed to determine whether MAGED1 regulates pineal Per3 expression and to define the intermediar...AIMS: The molecular mechanisms that regulate Per3 expression in the pineal gland remain incompletely understood. This study aimed to determine whether MAGED1 regulates pineal Per3 expression and to define the intermediary mechanism linking MAGED1 to transcriptional control of Per3. MATERIALS AND METHODS: Maged1 knockout mice and cultured cells were used to examine the relationship among MAGED1, NEUROD1, and Per3. Immunofluorescence, RNA fluorescence in situ hybridization, western blotting, proximity ligation assays, co-immunoprecipitation, ubiquitination assays, chromatin immunoprecipitation-qPCR, and luciferase reporter assays were performed to assess protein localization, protein-protein interaction, NEUROD1 stability, and Per3 promoter activity. KEY FINDINGS: MAGED1 showed time-of-day-dependent subcellular localization in the mouse pineal gland, with increased nuclear accumulation during the dark phase. Loss of Maged1 reduced pineal Per3 mRNA abundance and decreased NEUROD1 protein levels. MAGED1 did not show detectable enrichment at the Per3 promoter but interacted with NEUROD1 in pineal tissue and cultured cells. Mechanistically, MAGED1 maintained NEUROD1 protein abundance by limiting ubiquitin-mediated proteasomal degradation. NEUROD1 directly activated the Per3 promoter, and disruption of the MAGED1-NEUROD1 interaction reduced Per3 promoter activity. SIGNIFICANCE: These findings identify a MAGED1-NEUROD1-Per3 regulatory pathway in the pineal gland and provide a molecular mechanism by which MAGED1 supports pineal Per3 transcription.
Hypertension is increasingly recognized as an inflammatory-associated cardiovascular disorder in which cytokine-mediated endothelial dysfunction plays a central role. Tumor necrosis factor (TNF) is a key regulator linkin...Hypertension is increasingly recognized as an inflammatory-associated cardiovascular disorder in which cytokine-mediated endothelial dysfunction plays a central role. Tumor necrosis factor (TNF) is a key regulator linking oxidative stress, vascular inflammation, and blood pressure dysregulation, making it a potential therapeutic target. Andrographis paniculata, a medicinal plant rich in bioactive diterpenoids and flavonoids, has suggested cardiovascular benefits, although its molecular mechanisms remain insufficiently defined. In this study, an integrated computational strategy was employed to explore the potential molecular basis of TNF-centered interaction of A. paniculata compounds. Network pharmacology analysis identified TNF, IL6, and TP53 as central hubs within the hypertension-associated protein interaction network, highlighting the involvement of inflammatory signaling pathways. Among the investigated compounds, neoandrographolide emerged as a promising candidate for TNF-associated interactions under the applied computational conditions, supported by favorable binding affinity and stable ligand-target protein interactions. Molecular dynamics simulations further indicated that the neoandrographolide-TNF complex maintained structural stability, persistent hydrogen bonding, and energetically favorable interactions throughout the simulation period, suggested stable binding behavior under dynamic conditions. These findings suggest that TNF may represent a potential candidate target associated with the predicted antihypertensive activity of selected A. paniculata compounds, potentially contributing to the modulation of endothelial dysfunction and vascular inflammation associated with hypertension. These findings are based on computational predictions and require experimental validation. Overall, this study provides computational insights into the potential anti-inflammatory effects of A. paniculata, highlighting TNF as candidate pharmacological axis and supporting future experimental validation toward cytokine-targeted antihypertensive strategies.
AIMS: Renal interstitial fibrosis (RIF) drives chronic kidney disease (CKD) progression, with elevated soluble PD-1 (sPD-1) exacerbating chronic inflammation. This study aims to elucidate the pathogenic role of sPD-1 in...AIMS: Renal interstitial fibrosis (RIF) drives chronic kidney disease (CKD) progression, with elevated soluble PD-1 (sPD-1) exacerbating chronic inflammation. This study aims to elucidate the pathogenic role of sPD-1 in RIF and evaluate "Exo-PD1"-a novel engineered extracellular vesicle strategy designed to sequester circulating sPD-1-as a targeted therapeutic intervention to mitigate renal fibrosis. MATERIALS AND METHODS: We analyzed serum and renal biopsy samples from clinical CKD cohorts and three distinct mouse models-unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), and aristolochic acid I (AAI)-induced nephropathy-using ELISA, immunohistochemistry, and flow cytometry. Exo-PD1 was engineered by surface-functionalizing extracellular vesicles with avidin to load anti-PD-1 antibodies. The therapeutic efficacy and safety profiles of Exo-PD1 were systematically evaluated in vitro and in vivo. KEY FINDINGS: Elevated sPD-1 strongly correlated with RIF severity and T-cell hyperactivation in both patients and murine models, while exogenous sPD-1 exacerbated fibrosis. Exo-PD1 effectively sequestered circulating sPD-1, outperforming conventional antibodies through local adsorption. Furthermore, Exo-PD1 treatment significantly attenuated T-cell hyperactivation, blunted inflammatory responses, and reduced key fibrotic markers (α-SMA, collagen I) across models with minimal systemic toxicity. SIGNIFICANCE: sPD-1 acts as a critical mediator of renal fibrosis by disrupting immune homeostasis. The biocompatible Exo-PD1 platform effectively intercepts circulating sPD-1, disrupting the inflammation-fibrosis crosstalk and offering a highly translational therapeutic approach to halt CKD progression.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by aberrant hepatic lipid accumulation, yet the regulatory mechanisms underlying this process remain incompletely understood. Althou...BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by aberrant hepatic lipid accumulation, yet the regulatory mechanisms underlying this process remain incompletely understood. Although epitranscriptomic modifications have emerged as key regulators of hepatic lipid homeostasis, the role of N-methylguanosine (mG) modification in hepatic steatosis remains unclear. METHODS: Histological and immunohistochemistry studies were used to assess lipid deposition in free fatty acids (FFAs)-incubated AML12 and HepG2 cells, high-fat diet (HFD)-fed mice, and human liver samples from MASLD patients. Stable overexpression and knockdown of methyltransferase like 1 (METTL1) were established to investigate the effects of METTL1 on mG methylation and hepatocellular lipid metabolism. RNA-sequencing and RNA immunoprecipitation-quantitative-PCR (RIP-qPCR) analysis were performed to identify downstream molecular targets of METTL1. RESULTS: METTL1 expression was significantly increased in fatty liver tissues from both human and mouse compared with corresponding controls. METTL1 knockdown markedly attenuated FFAs-induced lipid accumulation in hepatocytes, whereas METTL1 overexpression exacerbated this phenotype. Notably, enforced ALOX15B expression reversed the attenuation of hepatic lipid accumulation induced by METTL1 knockdown. Mechanistically, METTL1 enhances the stability of ALOX15B mRNA through depositing mG modifications, thereby elevating ALOX15B protein levels, activating ERK1/2 pathway and promoting hepatic steatosis. CONCLUSIONS: Our findings identify a METTL1-ALOX15B epitranscriptomic regulatory axis in which METTL1-dependent mG modification of ALOX15B mRNA and promote hepatic steatosis, highlighting a potential therapeutic target for MASLD.
AIMS: To investigate the role of mitochondrial zinc (Zn) homeostasis in chemoresistance of osteosarcoma. MATERIAL AND METHODS: Zinc levels were measured in osteosarcoma cells treated with methotrexate (MTX). The expressi...AIMS: To investigate the role of mitochondrial zinc (Zn) homeostasis in chemoresistance of osteosarcoma. MATERIAL AND METHODS: Zinc levels were measured in osteosarcoma cells treated with methotrexate (MTX). The expression of SLC30A9 was analyzed in chemoresistant cells. SLC30A9 knockdown and overexpression osteosarcoma cell lines were constructed for functional studies, assessing mitochondrial zinc levels, mitochondrial function, and MTX sensitivity. Subcellular localization of SLC30A9 and its zinc efflux function were determined by immunofluorescence staining and mitochondrial zinc detection. The opening of the mitochondrial permeability transition pore (mPTP), release of mitochondrial DNA (mtDNA), activation of the cGAS-STING pathway, NF-κB signaling, and NDRG1 transcription were analyzed. Xenograft mouse models were established to evaluate the effect of SLC30A9 knockdown combined with a STING agonist. KEY FINDINGS: MTX treatment elevated mitochondrial zinc levels, leading to mitochondrial dysfunction. SLC30A9 was highly expressed in chemoresistant osteosarcoma cells. Knockdown of SLC30A9 caused abnormal mitochondrial zinc accumulation, mitochondrial dysfunction, and reversed MTX resistance. SLC30A9 was localized to mitochondria and mediated zinc efflux; its loss triggered mtDNA release into the cytosol via mPTP, activating the cGAS-STING pathway, which in turn promoted NF-κB-driven transcription of the pro-apoptotic molecule NDRG1. In vivo, SLC30A9 knockdown combined with STING-agonist3 enhanced the chemotherapeutic effect of MTX. SIGNIFICANCE: SLC30A9 maintains a low-zinc environment and mitochondrial integrity, thereby inhibiting mtDNA-mediated cGAS-STING pathway activation. Targeting SLC30A9 to disrupt this protective mechanism provides a novel therapeutic strategy for overcoming chemoresistance in osteosarcoma.
Zhu Y, Wang X, Li Y
… +15 more, Jiang W, Wu Z, Xu S, Tan Z, Wu A, Cai Y, Yang Y, Xiao X, Kuang X, Deng G, Zhang Y, Chen M, Li J, Zhang Y, Deng Z
Sci China Life Sci
· 2026 Jun · PMID 42364058
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RNA modifications have emerged as crucial regulators of cellular processes linked to aging. However, the dynamic changes in global RNA modification patterns during aging and their functional implications remain underexpl...RNA modifications have emerged as crucial regulators of cellular processes linked to aging. However, the dynamic changes in global RNA modification patterns during aging and their functional implications remain underexplored. Here, we comprehensively deciphered the RNA modification landscapes of total RNA, poly(A)-enriched mRNA, and tRNA-enriched fragments across six tissues in both young and aged mice, as well as in multiple cellular senescence models. Aged tissues exhibit overall decline of RNA modification abundance in tRNA, rather than in total RNA or mRNA, when compared to young tissues. Correspondingly, the expression of tRNA methyltransferases, METTL1 and TRMT1, also declines with aging and senescence. Modulation of these methyltransferases affects cellular senescence phenotypes; specifically, Mettl1 depletion results in accelerated aging in mice. Mechanistically, fibroblasts are identified as the primary cell type responsible for the aging traits induced by Mettl1 deficiency in mice. Reduced mG modification in fibroblasts leads to a decrease in the abundance of mG-modified tRNAs, which in turn impairs translation efficiency and protein synthesis, and contributes to an accumulation of tRNA-derived small RNAs (tsRNAs). Remarkably, these alterations affected the translation of genes involved in senescence and aging pathways. Our study provides a comprehensive landscape of tRNA modifications during aging and demonstrates that decreased activity of METTL1 in fibroblasts drives aging. Thus, modulation of tRNA modifications may be a promising strategy for improving healthy aging and alleviating age-associated disorders.
Zhang Y, Zhu H, Wang X
… +11 more, Dong W, Zhang M, Song X, Han D, Chai Q, Feng X, Wei X, Chen H, Li Y, Zhao L, Dai Q
Sci China Life Sci
· 2026 Jun · PMID 42364057
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Non-small cell lung cancer (NSCLC) remains a significant global health challenge, making the exploration of potential therapeutic targets critically important. In this study, we discovered that ZNF200 is highly expressed...Non-small cell lung cancer (NSCLC) remains a significant global health challenge, making the exploration of potential therapeutic targets critically important. In this study, we discovered that ZNF200 is highly expressed in NSCLC tissues and plays an oncogenic role by promoting cell proliferation and metastasis both in vitro and in vivo. Mechanistically, ZNF200 recruits DDX17 to the promoter region of RBPJ to upregulate the expression of RBPJ and activate the Notch signaling pathway. ZNF200 and DDX17 increase H3K4me3 enrichment at the RBPJ promoter. Furthermore, ZNF200 interacts with SETD1A to regulate H3K4me3 deposition, sustaining the transcriptional activity of the RBPJ promoter. Interestingly, DDX17 could maintain the protein stability of ZNF200 by inhibiting the ubiquitin-proteasome degradation pathway, which further increased the expression level of ZNF200 in the nucleus. Additionally, we revealed that miR-139 inhibits ZNF200 expression and that the introduction of miR-139 abrogates the increased cell proliferation and metastasis caused by ZNF200 over-expression. Overall, our work demonstrates the critical role and molecular mechanism of ZNF200 in regulating NSCLC development, highlighting the potential of targeting ZNF200 as an effective strategy in NSCLC treatment.
Yan P, Yang K, Xu W
… +10 more, Zhang J, Zhong W, Wang Z, Zhang J, Li W, Wang K, Zhao Y, Li D, Yu S, Kang X
Sci China Life Sci
· 2026 Jun · PMID 42364056
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As a crucial component of agriculture, livestock and poultry production supplies high-quality animal protein and is essential for the stability of food safety, ecological environment, human health, and global sustainabil...As a crucial component of agriculture, livestock and poultry production supplies high-quality animal protein and is essential for the stability of food safety, ecological environment, human health, and global sustainability. However, frequent epidemics have emerged as a major constraint on industry development, with traditional vaccine and drug-based controls facing challenges such as rapid pathogen mutation, environmental pollution, and drug residue risks. Disease-resistant breeding thus offers a crucial strategy for sustainable livestock farming, yet its progress is hindered by the lack of effective molecular targets for major epizootics. Extensive studies on adaptive immune regulation have identified numerous regulatory genes and molecular targets associated with disease resistance, offering significant potential for breeding applications. Nevertheless, despite the well-established role of adaptive immunity in human medicine, its utilization in livestock breeding remains largely underdeveloped. This review outlines the significance and current status of disease-resistant breeding, focuses on adaptive immune mechanisms, and proposes innovative strategies.
Xu Q, Sun L, Han X
… +3 more, Zhang Q, Jiang W, Zhu S
Sci China Life Sci
· 2026 Jun · PMID 42364055
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The role of the gut microbiome in type 2 diabetes (T2D) remains incompletely defined, particularly across microbial kingdoms and diverse populations. Here, we conducted a meta-analysis of 3,857 fecal metagenomes from six...The role of the gut microbiome in type 2 diabetes (T2D) remains incompletely defined, particularly across microbial kingdoms and diverse populations. Here, we conducted a meta-analysis of 3,857 fecal metagenomes from six international cohorts, profiling bacteria, fungi, archaea, and viruses. Using supervised machine-learning models trained on harmonized multi-kingdom profiles with cross-cohort validation, we identified conserved alterations in T2D, characterized by reduced bacterial and viral diversity and increased fungal and archaeal diversity. A cross-kingdom panel of 33 microbial markers derived from these models achieved robust diagnostic performance (AUR-OC=0.82), outperforming single-kingdom models. Notably, Saccharomyces cerevisiae was consistently depleted in T2D and inversely correlated with glycemic indices. In mice, oral S. cerevisiae supplementation improved glucose tolerance and insulin sensitivity while reducing the abundance of Eggerthella lenta and Klebsiella pneumoniae, bacterial taxa previously linked to adverse metabolic and inflammatory phenotypes. Together, our findings highlight the diagnostic value and mechanistic relevance of multi-kingdom microbial signatures in T2D and position S. cerevisiae as a potential fungal probiotic candidate for metabolic intervention.