AIMS: To determine the role of METTL3-mediated mA modification in hypoxic pulmonary arterial smooth muscle cells (PASMCs) over-proliferation and hypoxic pulmonary hypertension (HPH). MATERIALS AND METHODS: Human PAH tiss...AIMS: To determine the role of METTL3-mediated mA modification in hypoxic pulmonary arterial smooth muscle cells (PASMCs) over-proliferation and hypoxic pulmonary hypertension (HPH). MATERIALS AND METHODS: Human PAH tissues, smooth muscle-specific Mettl3 knockout mice, HPH models, scRNA-seq, hPASMCs culture, MeRIP-qPCR, RIP-qPCR, luciferase assay, and functional assays. KEY FINDINGS: METTL3 was upregulated in HPH PASMCs. Mettl3 depletion alleviated HPH and suppressed PASMC proliferation via FOXO1 upregulation. METTL3 reduced mA on FOXO1 3'UTR, decreased YTHDF2 binding, and stabilized FOXO1 mRNA. FOXO1 or YTHDF2 manipulation abolished METTL3-dependent effects. SIGNIFICANCE: We identify a METTL3-YTHDF2-FOXO1 axis driving PASMC proliferation in HPH, providing a potential therapeutic target.
Zhang Z, Jiang F, Li Z
… +12 more, Lin L, Qi B, Han D, Ran C, Mao S, Wang J, Zhou Z, Wang M, Li J, Wang G, Kang S, Zhang T
Sci China Life Sci
· 2026 May · PMID 42159959
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Animal gut microbiomes-comprising bacteria, archaea, fungi, viruses, and protozoa-are fundamental to host evolution, physiology, and ecosystem resilience. This review synthesizes 21st-century advances in their diversity,...Animal gut microbiomes-comprising bacteria, archaea, fungi, viruses, and protozoa-are fundamental to host evolution, physiology, and ecosystem resilience. This review synthesizes 21st-century advances in their diversity, spatiotemporal dynamics, and functional roles across the animal kingdom. Although high-throughput metagenomics has transformed the field, major biases remain: most studies still focus on domesticated vertebrates and fecal samples, leaving substantial "microbial dark matter" in wild hosts, invertebrates, and non-bacterial domains unexplored. We highlight how gut microbiomes mediate adaptation to environmental extremes, including hypoxia, temperature stress, and toxins, and how industrialization disrupts these communities, contributing to biodiversity loss and disease risk. We further integrate eco-evolutionary theory, multi-omics, and spatial modeling to clarify cross-kingdom interactions and functional networks. Finally, we discuss translational applications-including probiotics, fecal microbiota transplantation (FMT), phage therapy, and synthetic consortia-and emphasize the need for global collaborative initiatives, artificial intelligence (AI)-driven discovery, and standardized databases to unlock the full potential of animal gut microbiomes for biodiversity conservation, climate resilience, and planetary health in the coming decades.
Zhang J, Chen Y, Liu B
… +9 more, Qin Y, Luan Y, Yin H, Liu W, Chen L, Zhai J, Pei Y, Long Y, Jin Z
Sci China Life Sci
· 2026 Jul · PMID 42159957
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Plants rely on gasotransmitters like hydrogen sulfide (HS) to coordinate stress adaptation, yet how HS orchestrates spatiotemporal responses across cell types remains unknown. Here, we generated a high-resolution single-...Plants rely on gasotransmitters like hydrogen sulfide (HS) to coordinate stress adaptation, yet how HS orchestrates spatiotemporal responses across cell types remains unknown. Here, we generated a high-resolution single-nucleus RNA sequencing (snRNA-seq) atlas of Chinese cabbage (Brassica rapa L. ssp. pekinensis) leaves, capturing the dynamic transcriptional response to HS over the course of 24 h. We identified 18 transcriptionally distinct clusters corresponding to nine major leaf cell types. HS induces globally coordinated transcriptional reprogramming, prominently featuring the broad activation of defense responses across cell types. We identified two HS-induced genes that enhance drought tolerance. BrHSP23.6, initially confined to guard cells, becomes globally expressed under HS fumigation and is required for HS-mediated enhancement of photosynthetic performance and drought tolerance. Similarly, BrNTF2, a de novo induced nuclear transport factor, is essential for HS-dependent stomatal regulation and drought resilience. In parallel, HS spatiotemporally activates hormone and sulfur metabolic pathways. Our study deciphers a spatiotemporal pattern of HS signaling at single-cell resolution, providing a new framework for understanding how gasotransmitters orchestrate plant adaptation.
Sci China Life Sci
· 2026 May · PMID 42144507
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Chronic inflammatory diseases are increasingly recognized as dynamic and spatially complex disorders involving diverse immune and nonimmune components. In this review, we introduce the concept of the inflammatory ecosyst...Chronic inflammatory diseases are increasingly recognized as dynamic and spatially complex disorders involving diverse immune and nonimmune components. In this review, we introduce the concept of the inflammatory ecosystem as a framework for understanding how inflammation is organized across distinct anatomical and functional zones, termed inflammazones-ranging from local to systemic. We first examine how immune cells, through activation, differentiation, and mimicry, transition into inflammatory phenotypes. We then explore the transformation of non-immune cells-such as keratinocytes, fibroblasts, and endothelial cells-into active participants in inflammation, facilitated by intercellular crosstalk and cytokine exchange. Central to these processes are biophysical and molecular mechanisms such as phase separation, signalosome formation, and exosome-mediated communication, which organize and amplify inflammatory signals. We further delineate how these cellular events lead to pathological changes in organ-specific contexts, using diseases like sarcoidosis and psoriasis as model systems. Finally, we discuss the therapeutic implications of this ecosystem-based approach, highlighting how zone-specific interventions and multi-omics-guided precision medicine can transform the treatment landscape of inflammatory diseases. This conceptual model advances our understanding of inflammation as an integrated, spatially regulated process with broad clinical relevance.
Zhuang W, Bai H, Zhao J
… +23 more, Li W, Yu J, Wang Z, Duan J, Hao X, Wang Y, Liu Y, Wang L, Lin L, Wan R, Sun B, Xu J, Fei K, Fan Y, He W, Liu Z, Fan L, He D, Gao R, Yang Y, Ying J, Zhong J, Wang J
Sci China Life Sci
· 2026 May · PMID 42144506
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Epidermal growth factor receptor (EGFR) exon 19 deletions (19del) in non-small cell lung cancer (NSCLC) confer sensitivity to tyrosine kinase inhibitors (TKIs). However, the efficacy of the individual EGFR 19del variant...Epidermal growth factor receptor (EGFR) exon 19 deletions (19del) in non-small cell lung cancer (NSCLC) confer sensitivity to tyrosine kinase inhibitors (TKIs). However, the efficacy of the individual EGFR 19del variant remains unclear. This study aims to dissect the structural disparities of various EGFR 19del mutations and associate these variations with clinical outcomes. Here, a total of 399 patients from two cancer centers covering 35 distinct EGFR 19del variants were included in this study. Through molecular docking analysis, we identified a structure-based subgroup of EGFR 19del mutations, termed CLASS 3G (E746_A750>X, E746_S752>V, L747_A750>P, and L747_T751>P). In silico and in vitro analysis demonstrated that CLASS 3G mutations had reduced binding affinity to third-generation EGFR-TKIs. Clinically, patients with CLASS 3G showed inferior PFS to non-CLASS 3G after receiving third-generation EGFR-TKIs (first-line progression-free survival: 12.8 vs. 25.6 months, P=0.045; second-line progression-free survival: 7.7 vs. 15.2 months, P=0.039). This finding was further validated in an independent cohort, confirming consistent results with the primary analysis. Additionally, we found that CLASS 3G mutations derived significant benefits from third-generation EGFR-TKIs plus chemotherapy compared with third-generation EGFR-TKIs monotherapy (32.5 vs. 12.8 months, P=0.0038). Our study identified a subgroup of EGFR 19del that responded poorly to third-generation EGFR-TKIs based on structural features of the EGFR tyrosine kinase domain. These patients benefit substantially from the combination treatment of third-generation EGFR-TKIs plus chemotherapy.
AIMS: Advanced glycation end products (AGEs), particularly AGE-modified albumin (AGE-BSA), have been implicated in vascular inflammation and endothelial dysfunction, while neutrophil extracellular traps (NETs) are known...AIMS: Advanced glycation end products (AGEs), particularly AGE-modified albumin (AGE-BSA), have been implicated in vascular inflammation and endothelial dysfunction, while neutrophil extracellular traps (NETs) are known to aggravate endothelial injury. Here, we investigated whether AGE-BSA directly promotes endothelial inflammatory and thrombotic activation, modulates neutrophil oxidative stress and NET formation, and may enhance NET-induced endothelial inflammation. MATERIALS, METHODS, AND KEY FINDINGS: In human aortic and human umbilical vein endothelial cells, two different endotoxin-free AGE-BSA formulations did not or only minimally alter the expression or secretion of inflammatory (IL-6, IL-1β, CCL2) or thrombotic (VCAM-1, tissue factor) markers. In parallel, neutrophils from healthy donors were exposed to BSA or AGE-BSA, and neither basal nor PMA-stimulated NET formation nor reactive oxygen species (ROS) production were affected. Furthermore, endothelial cells stimulated with PMA-induced NETs generated in the presence of BSA or AGE-BSA showed comparable induction of inflammatory and pro-thrombotic genes, indicating that AGE-BSA does not modify NET-mediated endothelial activation. Flow cytometry revealed higher intracellular than surface RAGE levels in endothelial cells and a low surface expression in neutrophils, potentially limiting AGE-RAGE signaling at the plasma membrane. SIGNIFICANCE: Collectively, these data demonstrate that, under the conditions tested, endotoxin-free AGE-BSA has no or minimal pro-inflammatory effect on human aortic or umbilical vein endothelial cells, neutrophil NET and ROS formation, nor NET-driven endothelial inflammation, potentially due to a limited surface RAGE availability or downstream signaling capacity. This challenges the view of an inherent pro-inflammatory effect of AGE-modified BSA and highlights the significance of important cell type- and context-specific contributors.
This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail....This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.
Wang Y, Fan Z, Chu X
… +11 more, Zhou K, Wang T, Guan J, Hu R, Li A, Li W, Liu X, Zhang X, Wang X, Miao YL, Zhou J
Sci China Life Sci
· 2026 May · PMID 42141343
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Oocyte developmental competence relies on the coordinated progression of nuclear and cytoplasmic maturation, driven by the precise translational regulation of stored maternal mRNAs. Using an integrative transcriptomic an...Oocyte developmental competence relies on the coordinated progression of nuclear and cytoplasmic maturation, driven by the precise translational regulation of stored maternal mRNAs. Using an integrative transcriptomic and translatomic approach, we characterized the dynamic translational landscape of porcine oocytes during maturation. Through cross-species analysis with human and mouse data, we discovered conserved and species-specific translational programs, highlighting a greater translational resemblance between porcine and human oocytes. Comparative profiling further revealed aberrant maternal mRNA translational activation and degradation during in vitro maturation (IVM) vs. in vivo conditions, including defective translational activation of GPLD1 and HNRNPK, which were pinpointed as mechanisms compromising oocyte quality and embryonic development. To further dissect how translational regulation coordinates oocyte nuclear and cytoplasmic maturation, we employed a dbcAMP-induced cell cycle-synchronized model to identify gene sets with cell cycle-dependent and -independent translational activation. Characterization of these groups identified cytoplasmic polyadenylation element binding protein 1 (CPEB1) as a key orchestrator within the translational regulatory network, where it specifically activates the translation of cell cycle-dependent maternal factors through the cytoplasmic polyadenylation elements (CPEs) within 3'UTRs. Collectively, these findings elucidate key translational mechanisms during porcine oocyte maturation and offer a molecular basis for improving in vitro maturation and reproductive efficiency in livestock.
Huang H, Li Y, Song Q
… +13 more, Yuan L, Yang Y, Zhu M, Sun R, Hu Y, Xiong C, Ni T, Liu Y, Ruiz-Linares A, Zhang G, Liu F, Peng Q, Wang S
Sci China Life Sci
· 2026 May · PMID 42132992
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Aging exhibits both systemic and organ-specific components, yet existing models struggle to disentangle their shared versus distinct biological determinants at the population level. We present a structural decomposition...Aging exhibits both systemic and organ-specific components, yet existing models struggle to disentangle their shared versus distinct biological determinants at the population level. We present a structural decomposition framework that partitions seven organ-based biological age gaps (BAGs) into a Common BAG (CBAG) and seven Organ-Specific BAGs (OSBAGs) in 501,388 UK Biobank participants. This dual-axis model outperforms undecomposed body/organ BAG approaches in predicting lifespan, healthspan, and organ-specific disease risk. A large-scale aging GWAS identifies 747 novel loci, complemented by integrative proteomic and metabolomic analyses that reveal causal and druggable targets, including CST1. Pathway-guided multi-omics demonstrates a modular aging architecture, with CBAG reflecting cross-tissue regulators (e.g., FOXO3) and OSBAGs capturing organ-restricted effectors (e.g., UMOD). Drug-aging profiling uncovers organ-specific pro-aging effects consistent with known toxicities that are largely missed by undecomposed models. Sex-stratified analyses further reveal divergent molecular trajectories between males and females. All findings are integrated into HONOR, the first open-access atlas for structural aging and multi-omics translation.
He WT, Xing X, Wang F
… +3 more, Li L, Cheng Y, Yao G
Sci China Life Sci
· 2026 May · PMID 42132991
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Microorganisms within the tumor microenvironment represent an important but still underexplored dimension of cancer biology, influencing genomic stability, immune responses, metabolism, and therapeutic efficacy. Although...Microorganisms within the tumor microenvironment represent an important but still underexplored dimension of cancer biology, influencing genomic stability, immune responses, metabolism, and therapeutic efficacy. Although recent findings underscore the significance of the tumor microbiome, distinguishing causal "drivers" from non-functional "passengers" remains a major challenge, particularly in the context of extremely low microbial biomass and high contamination risk. Advances in next-generation sequencing, single-cell genomics, and spatial transcriptomics are now transforming the field, enabling profiling that extends beyond descriptive catalogs toward functional and spatial resolution. Here, we introduce a unified, contamination-aware analytical framework tailored to the unique constraints of tumor microbiome studies, integrating standardized sampling, library construction, host-depletion strategies, and multi-layer computational analysis. We also evaluate emerging technologies that couple microbial identity with host-cell states at single-cell and spatial resolution, offering new opportunities to functionally map tumor-associated microorganisms. Furthermore, we propose that the integration of orthogonal validation strategies-combining imaging, spatial transcriptomics, in situ microbial profiling, and sequencing-is poised to define the next stage of mechanistic tumor microbiome research. Together, these perspectives outline key methodological inflection points and future directions toward a mechanistic understanding of tumor-microbe interactions and their therapeutic potential.
Qian W, Chen Q, Hu H
… +3 more, Wang S, Yao H, Tang H
Sci China Life Sci
· 2026 May · PMID 42132990
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Intracellular organelles are pivotal for maintaining cellular homeostasis, with lipids serving as key mediators of inter-organellar contact and communication. However, the limited understanding of lipid chemical diversit...Intracellular organelles are pivotal for maintaining cellular homeostasis, with lipids serving as key mediators of inter-organellar contact and communication. However, the limited understanding of lipid chemical diversity and composition has constrained research into lipid-mediated organellar functions. The A549 cell lines, a widely used human non-small cell lung cancer model in both basic research and drug discovery, provide an ideal system for investigations. In this study, we generated the quantitative lipidomic atlas covering seven subcellular compartments, including mitochondria, ER, Golgi apparatus, nucleus, exosome, lysosome and plasma membrane in A549 cells. This atlas encompasses appropriately 1,400 lipid species across 40 subclasses and systematically characterizes the proportional composition and distinct features of each organelle. We analyzed the key features, including lipid species distribution, unsaturation and chain length patterns, as well as the ratios of polyunsaturated fatty acids to monounsaturated and saturated fatty acids (PUFA:MUFA+SFA) and cylindrical to non-cylindrical lipids. Causal connection and pair-by-pair correlation analyses revealed that the ER acts as the primary source of lipid flow, with mitochondria as its terminal. Specifically, glycosylceramide and dihexosylceramides (Hex2Cer) emerge as central hubs exhibiting significant correlations with other lipids across the seven subcellular lipidomes. Taken together, this study establishes a reference lipidome for seven major organelles, maps their distinct lipidomic characteristics and the correlations of lipid-mediated interorganelles, and provides new insights into the lipid-based communication networks in cancer cells.
Zhang Y, Zheng Y, Chen B
… +6 more, Li X, Zhang T, Xu L, Ma J, Ma X, Li Y
Sci China Life Sci
· 2026 May · PMID 42132988
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Severe burn injury induces a prolonged hypermetabolic state that is associated with undesirable metabolic consequences. Heat shock factor 1 (HSF1) is the predominant transcription factor that responds to thermal stress a...Severe burn injury induces a prolonged hypermetabolic state that is associated with undesirable metabolic consequences. Heat shock factor 1 (HSF1) is the predominant transcription factor that responds to thermal stress and has been reported to orchestrate the browning gene program of subcutaneous white adipose tissue (sWAT), thereby promoting energy expenditure. However, the role of sWAT HSF1 in the pathogenesis of burn injury remains unclear. In this study, we report that burn injury notably upregulates the expression of HSF1 in sWAT. Moreover, the genetic ablation of HSF1 in adipose tissues attenuated the burn-induced sWAT browning and lipolysis, circulating lipid dysfunction, and liver injury. Conversely, specific overexpression of the active form of HSF1 in sWAT exacerbated these phenotypes. Notably, we found that burn injury largely suppressed sWAT smooth muscle-related gene programs and shifted toward browning gene programs. Mechanistically, HSF1, in cooperation with PRDM16, drives this phenotypic switch by directly inhibiting the expression of Myh11, which is the smooth muscle marker for sWAT reprogramming. Furthermore, the pharmacological inhibition of HSF1 with DTHIB ameliorated burn injury. Overall, these findings highlight that sWAT HSF1 is a key mediator of pathological hypermetabolism following severe burn injury.
Li M, Huo Y, Zhu S
… +7 more, Cao Q, Wan J, Li Y, Pitts H, Nolan D, Loor JJ, Xu C
Sci China Life Sci
· 2026 May · PMID 42128991
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Palmitic acid (PA), the most abundant saturated fatty acid in bovine blood, serves not only as an important energy precursor but also induces cellular dysfunction when in excess. This study aimed to elucidate the mechani...Palmitic acid (PA), the most abundant saturated fatty acid in bovine blood, serves not only as an important energy precursor but also induces cellular dysfunction when in excess. This study aimed to elucidate the mechanisms underlying PA-induced mammary gland injury and to identify potential therapeutic strategies for improving mammary health and milk quality. In this study, the STAT3 signaling pathway was significantly downregulated, apoptosis was upregulated, and lipid metabolism was dysregulated in the mammary glands during ketosis, a typical fatty acid surfeit situation. To establish a direct causal role of PA and STAT3, we employed an in vitro MAC-T cell model, where exogenous PA treatment recapitulated the mammary injury phenotype observed in vivo. Furthermore, treatment with Colivelin, a STAT3 activator, alleviated PA-induced apoptosis and fatty acid oxidation impairment in bovine mammary epithelial cells. Cleavage under targets and tagmentation analysis revealed that PA treatment suppressed the binding of STAT3 to the CPT1A promoter. CPT1A knockdown mitigated the protective effects of Colivelin against PA-induced lipotoxicity. These findings suggest that excessive PA impairs fatty acid oxidation in mammary cells through the inhibition of STAT3 activity, thereby contributing to mammary gland injury and reduced milk yield in dairy cows.
Somatostatin (SST)-expressing neurons are predominantly inhibitory and co-release the fast-acting neurotransmitter γ-aminobutyric acid (GABA). However, the role of GABAergic transmission from SST neurons remains incomple...Somatostatin (SST)-expressing neurons are predominantly inhibitory and co-release the fast-acting neurotransmitter γ-aminobutyric acid (GABA). However, the role of GABAergic transmission from SST neurons remains incompletely understood. Here, we showed that mice with inactivation of the gene encoding the vesicular GABA transporter (VGAT) specifically in SST-expressing cells exhibited decreased food intake, weight loss, and hypoglycemia, despite increased activity of orexigenic agouti-related protein-expressing neurons, and died before reaching 4 weeks of age. Additionally, loss of GABAergic transmission from SST neurons led to overactivation of brainstem areas that induce meal termination and anorexia, including the nucleus of the solitary tract and the lateral parabrachial nucleus (PBN), particularly calcitonin gene-related peptide-expressing neurons. Remarkably, when SST-specific VGAT knockout mice were exposed to a highly palatable diet, their precocious death was partially prevented. The exclusive source of SST innervation to the PBN was from neurons of the lateral central nucleus of the amygdala (CEA) and the oval subdivision of the bed nucleus of the stria terminalis (BNST). Furthermore, CEA and BNST neurons exhibited distinct neurochemical identities and connectivity compared with protein kinase C-δ neurons. In conclusion, GABAergic transmission from SST neurons is essential for postnatal survival and regulates the activity of key neurocircuits that control food intake.
Anti-cancer peptides (ACPs) selectively kill tumor cells through membrane disruption, intracellular target engagement, and immune activation. Recent structural and computational advances have clarified structure-activity...Anti-cancer peptides (ACPs) selectively kill tumor cells through membrane disruption, intracellular target engagement, and immune activation. Recent structural and computational advances have clarified structure-activity relationships, enabling rational engineering via cyclisation, D-amino acid incorporation, and nanoparticle delivery. This review integrates current understanding of ACP-cellular interactions, with emphasis on clinical-stage agents and the integration of artificial intelligence in peptide design. Key barriers like proteolytic instability, tumor penetration, and acquired resistance are evaluated alongside emerging solutions, including stapled peptides, tumor-activatable linkers, and combination regimens. With more than 80 candidates in trials and the first approvals anticipated within 3-5 years, ACPs are positioned to complement personalized oncology.