Science China Life Sciences最新文献

Host-microbiome interactions are crucial for physiological homeostasis and disease progression. While traditional microbiome research provided foundational insights, multi-omics approaches enable a more comprehensive and systems-level understanding. However, integrating multi-omics data presents significant methodological challenges, including inconsistent sample coverage, heterogeneous data formats, and complex analytical workflows, which collectively impair reproducibility and reliability. To address these critical challenges, we developed the EasyMultiProfiler (EMP), a streamlined and efficient analytical workflow. EMP utilizes SummarizedExperiment and MultiAssayExperiment classes to establish a unified multi-omics data storage and analysis framework. Its architecture comprises five interconnected functional modules: data extraction, preparation, support, analysis, and visualization, integrated into a user-friendly and natural language-style workflow. This design offers an efficient and standardized solution, directly resolving data integration issues, workflow standardization, and result reproducibility. EMP provides researchers and clinicians with a robust and flexible platform to systematically extract biologically relevant insights from complex multi-omics datasets, overcoming key barriers in contemporary microbiome research.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, accounting for approximately 17.9 million deaths each year (31% of all global deaths). Cardiovascular aging (CVA) not only contributes to the aging of other organ systems, leading to systemic aging in individuals, but also induces CVDs that impose serious health challenges and exacerbate CVA. Notably, non-coding RNAs (ncRNAs) such as miRNAs, lncRNAs, and circRNAs have emerged as key players in CVA and associated CVDs (AR-CVDs) by acting as pro-aging, anti-aging, or dual-regulating ncRNAs. They influence both vascular aging and cardiac aging processes through modulating pro-aging or anti-aging substrates and triggers, leading to cellular senescence and CVA-related phenotypes and associated pathological processes, including hypertension, atherosclerosis, coronary heart disease, cardiac hypertrophy, heart failure, and arrhythmias. This review aims to provide an overview of the current understanding of ncRNAs in CVA and AR-CVDs, focusing on the published studies that utilize in vitro and in vivo models of aging and aging-related cardiovascular pathophysiological processes. It does not aim to exhaustively cover all ncRNA studies unrelated to aging but to present a more holistic and integrated perspective on the diverse roles of miRNAs, lncRNAs, and circRNAs in the context of CVA and AR-CVDs. In doing so, we will explore both shared and unique aspects of ncRNAs from various angles, shedding light on their regulatory roles in CVA and AR-CVDs, which may offer insights into the current state and future directions of the field. By integrating recent findings and ongoing research, this review seeks to elucidate the intricate network of ncRNAs in CVA and AR-CVDs, paving the way for novel approaches to combat one of the most pressing health challenges of our time.

Gynecological cancer poses a serious threat to women's health. Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers, substantial challenges persist, including limited response rates, inevitable resistance, and adverse effects. In recent years, a milestone in gynecological cancer therapy has been the approval of antibody-drug conjugates (ADCs). In this review, we provide a comprehensive overview of the structural features, mechanisms of action, and molecular characteristics of ADCs that have been approved and are currently under development. Their clinical applications and associated challenges have also been highlighted. Finally, we discuss the prospects of ADCs in the treatment of gynecological cancers.

Lipid metabolism disorders and increased angiogenesis play key roles in the tumorigenesis of hepatocellular carcinoma (HCC). Intracellular metal ion disorders such as cuproptosis and ferroptosis have been progressively identified. However, whether copper ions have other effects outside the already recognized mechanisms of cell death is just as worthy of investigation. In particular, the effects on lipid metabolism and angiogenesis have important roles in the development of HCC. Our study revealed that disulfiram (DSF), a copper ion carrier, not only had a significant antitumor effect in vitro and in vivo, but also significantly inhibited angiogenesis and reversed abnormal lipid metabolism. Through transcriptome analysis, m¹A methylation analysis, and functional validation, we identified c-FOS as a key target in DSF-induced methylation changes. In summary, DSF can reduce the modifications of c-FOS caused by the m¹A methyltransferase TRMT10C, then regulate downstream genes MCAM and PCSK9, ultimately affecting angiogenesis and lipid metabolism. Moreover, high levels of expression of TRMT10C and PCSK9 in human HCC tumor tissues were associated with poor prognosis, while c-FOS showed the opposite pattern, confirming that the TRMT10C-c-FOS-PCSK9 axis is an important mechanism in HCC. In conclusion, copper ion carrier-DSF promotes the expression of c-FOS by inhibiting the m¹A methyltransferase TRMT10C, thereby reversing the dysregulation of lipid metabolism and inhibiting angiogenesis in HCC.

Grain chalkiness is a detrimental trait that significantly reduces the quality and economic value of rice, yet its regulatory mechanisms remain poorly understood. To identify genetic loci regulating grain chalkiness, we performed high-throughput activation tagging-based T-DNA insertion mutagenesis in the model rice variety (Oryza sativa L.) Kitaake. We found that a loss-of-function mutation in OsMADS18 resulted in enhanced grain chalkiness, reduced plant height, and delayed flowering time. Through yeast two-hybrid (Y2H) screening, we identified OsbZIP60 as an interacting partner of OsMADS18. Further analysis revealed that OsMADS18 directly bound to and positively regulated the expression of chalkiness-related genes, including Chalk5, FLO7, OsPK2, and OsNF-YB1, which are also transcriptional targets of OsbZIP60. Genetic analysis revealed that the osbzip60-1 osmads18-1 double mutant phenocopied the chalkiness of osbzip60-1, with more severe defects than osmads18-1, placing OsbZIP60 downstream of OsMADS18 in grain chalkiness control. Additionally, OsMADS18 positively regulates grain weight, starch content, amylose content, and protein levels under high-temperature conditions by modulating the expression of unfolded protein response (UPR) genes, including OsbZIP50, OsBiP1, OsBiP2, OsBiP3, OsBiP4, and OsBiP5. The double mutant showed increased chalkiness under heat stress, underscoring the role of the OsMADS18-OsbZIP60 interaction in thermotolerance. These findings indicate that OsMADS18-mediated UPR, enhanced by its interaction with OsbZIP60, is critical for mitigating grain chalkiness under stress. We propose a novel model wherein the OsMADS18-OsbZIP60 transcriptional module centrally governs this trait in rice.

The decline in oocyte quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice identifies morphologically defective aged oocytes with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is down-regulated with oocyte aging, and Plat knockdown increases oocyte susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through PCD. Supplementing exogenous tPA in vitro oocyte maturation cultures reduces the defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from PCD, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.

Age-related macular degeneration (AMD), particularly its atrophic (dry) form, is a leading cause of irreversible blindness in the elderly. Limited treatment efficacy stems from its complex pathogenesis, highlighting an urgent need for novel therapeutic targets. This study investigates the contribution of the choroidal immune microenvironment, focusing on intercellular communication involving resident fibroblasts-a cell type whose role in AMD remains poorly defined. By analyzing single-cell RNA sequencing data from human choroid, we interrogated crosstalk between fibroblasts, macrophages, and NK/T cells, identifying interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) signaling pathways as central mediators. We demonstrate that activated choroidal fibroblasts release key inflammatory mediators, including IL6, CCL2, CSF1, CXCL9, and CXCL10, which functionally recruit macrophages and CD8⁺ T cells, thereby shaping the local immune landscape. Critically, targeting these pathways in vivo using TAPI-1 (inhibiting TNFα processing) and Tofacitinib (inhibiting IFNγ signaling) significantly ameliorated retinal, RPE, and choroidal pathology in a NaIO₃-induced murine model of dry AMD. Our findings underscore the pathogenic role of fibroblast-mediated choroidal inflammation driven by TNFα and IFNγ signaling in dry AMD, presenting these pathways as promising therapeutic targets.

Emerging evidence suggests that long non-coding RNAs (lncRNAs) play crucial roles in ferroptosis regulation, yet the detailed mechanisms remain largely elusive. In this study, we identify LINC00942, a ferroptosis-associated lncRNA, which localizes to mitochondria and coordinates ferroptosis and tumorigenesis by modulating mitochondrial function. Bioinformatic analysis establishes that LINC00942 is specifically overexpressed in hepatocellular carcinoma (HCC), and its high expression is closely associated with poor patient prognosis. Both in vitro and in vivo experiments demonstrate that LINC00942 promotes HCC cell proliferation, migration, and invasion. Furthermore, suppression of LINC00942 disrupts mitochondrial function, impairs energy metabolism, and increases mitochondrial lipid peroxidation and reactive oxygen species (ROS) levels, rendering HCC cells more susceptible to ferroptosis. Mechanistically, LINC00942 interacts with G-rich sequence factor 1 (GRSF1) and subsequently translocates to the mitochondria. Within mitochondria, LINC00942 facilitates the binding of GRSF1 to complex I mRNA, thereby enhancing the translation efficiency of complex I subunits. The resulting upregulation of complex I protein levels strengthens its enzymatic activity and promotes mitochondrial oxidative phosphorylation, while concurrently suppressing ferroptosis. In addition, DNA demethylation and CREB1 contribute to the transcriptional activation of LINC00942 in HCC. Notably, administration of GalNAc-conjugated siRNA targeting LINC00942 effectively suppresses tumor growth in orthotopic xenograft models. Collectively, these findings underscore the oncogenic function of LINC00942 through the modulation of mitochondrial bioenergetics and ferroptosis, highlighting it as a promising therapeutic target for HCC.