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Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins （a process known as ferritinophagy）, in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritino- phagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis.

O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found via in vitro cell-based and in vivo mouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes. Yap is a transcriptional factor involved in tumorigenesis. Here the authors show that a previously unknown post-translational modification of Yap, O-GlcNAcylation, increases its transcriptional activity and is required for high glucose-induced liver cancer development.

Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. YAP has been reported to play a pivotal role in controlling ferroptotic death, and the expression of YAP is enhanced and stabilized by O-GlcNAcylation. However, whether O-GlcNAcylation can increase the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis remains unknown. In the present study, we found that O-GlcNAcylation increased the sensitivity of HCC cells to ferroptosis via YAP. Moreover, YAP increased the iron concentration in HCC cells through transcriptional elevation of TFRC via its O-GlcNAcylation. With YAP knockdown or YAP-T241 mutation, the increased sensitivity to ferroptosis induced by O-GlcNAcylation was abolished. In addition, the xenograft assay confirmed that O-GlcNAcylation increased ferroptosis sensitivity via TFRC in vivo. In summary, we are the first to find that O-GlcNAcylation can increase ferroptosis sensitivity in HCC cells via YAP/TFRC. Our work will provide a new basis for clinical therapeutic strategies for HCC patients.

Background N 6 -Methyladenosine (m 6 A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m 6 A modification in hepatoblastoma (HB). Methods We used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m 6 A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m 6 A-Seq was used to profiled m 6 A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB. Results In this research, we discovered that m 6 A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m 6 A modification. We also profiled m 6 A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m 6 A is highly expressed in hepatoblastoma tumors. Also, m 6 A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m 6 A mRNA methylation contributes significantly to regulate the Wnt/β-catenin pathway. Reduced m 6 A methylation can lead to a decrease in expression and stability of the CTNNB1. Conclusion Overall our findings suggest enhanced m 6 A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m 6 A modification in HB.

Some types of circular RNA (circRNA) are aberrantly expressed in human diseases including hepatocellular carcinoma (HCC). However, its regulation mechanism and diagnostic roles are largely unknown. Here, we identified that circRNA_104075 (circ_104075) was highly expressed in HCC tissues, cell lines and serum. Mechanistically, HNF4a bound to the −1409 to −1401 region of the circ_104075 promoter to stimulate the expression of circ_104075. Moreover, circ_104075 acted as a ceRNA to upregulate YAP expression by absorbing miR-582-3p. Interestingly, an N 6 -methyladenosine (m 6 A) motif was identified in the 353–357 region of YAP 3′UTR, and this m 6 A modification was essential for the interaction between miR-582-3p and YAP 3′UTR. Further, the diagnostic performance of circ_104075 was evaluated. The area under the receiver operating characteristic (AUC-ROC) for circ_104075 was 0.973 with a sensitivity of 96.0% and a specificity of 98.3%. Collectively, we determined that circ_104075 was highly expressed in HCC and elucidated its upstream and downstream regulatory mechanisms. circ_104075 additionally has the potential to serve as a new diagnostic biomarker in HCC. Targeting circ_104075 may provide new strategies in HCC diagnosis and therapy.

Understanding the heterogeneity of epigenetic modifications within single cells is pivotal for unraveling the nature of the complexity of gene expression and cellular function. In this study, we have developed a strategy based on multichrome encoding and “AND” Boolean logic recognition for multiplexed, spatially resolved imaging of single-cell RNA epigenetic modifications, termed as PRoximity Exchange-assisted Encoding of Multichrome (PREEM). Through the implementation of this strategy, we can now map the expression and nuclear distribution of multiple site-specific RNA N6-methyladenosine (m 6 A) modifications at the single-molecule resolution level in single-cells, and reveal the previously unknown heterogeneity. Notably, we demonstrate how these patterns change after treatment with various drugs. Moreover, cyclic imaging with tailed DNA self-assembly further suggest the scalability and adaptability of PREEM’s design. As an innovative epigenetic modification imaging tool, PREEM not only broadens the horizons of single-cell epigenetics research, enabling joint analysis of multiple targets beyond the limitations of imaging channels, but also reveals cell-to-cell variability, thereby enhancing our capacity to explore cellular functions. Understanding the heterogeneity of epigenetic modifications is pivotal for unraveling cellular functions. Here, the authors developed a strategy based on multichrome encoding and “AND” Boolean logic recognition, termed as PREEM, for multiplexed imaging of m6A modifications of single-cell RNA.

This paper establishes a compartment model describing the propagation of injurious information among a well-mixed population. We define the information’s injuriousness as the people practicing the information being injured and leaving the system. Some informed people practice the information and are active, while others do not practice and are inactive. With the recovery resources fixed, the two groups of informed people’s recovering rates are normalized considering the information features. The stability of the nonlinear system is thoroughly studied. Analyzing the reproduction number of the injurious information, we find that in general parameter space, when there are people in an informed compartment, it is not always necessary to consider their recovery resource allocation. Instead, only when their proportion reaches a critical point should it be allocated. Unless the people in an informed compartment form a certain proportion, we can take a laissez-faire attitude towards them. In a more realistic parameter space, once inactive informed people exist, they should be allocated recovery resources. On the one hand, when the recovering rate rises, the focus on both groups of informed people is necessary for more situations. On the other hand, when the rate of active informed people leaving the system rises, ignoring active informed people benefits removing the injurious information in more cases. The model provides qualitative ways in the scenarios of removing injurious information.

Biomolecular condensates are membraneless compartments involved in a wide range of cellular processes. Despite their fundamental role in the spatiotemporal regulation of cellular functions, tools for precisely manipulating phase-separated condensates remain limited, and effective methods for discovering and functionalizing tunable phase separation modules from natural proteins are lacking. Here we present a rational engineering approach for androgen receptor (AR) and its clinically used drugs to create a chemical genetic platform, ARDrop, enabling condensates formation and dissolution. This platform is applied to a diverse set of proteins to achieve intended cellular functions, ensuring robust and long-lasting functionality through stable liquid-like properties. Our work develops a powerful toolkit for reversible manipulation of condensates that can be used for dissection of complicated cell signaling, laying the foundation for engineering designer condensates for synthetic biology applications. Tools for precisely manipulating phase-separated condensates remain limited. Here authors present an engineered system based on the androgen receptor, where clinically used drugs can be used to control the formation and dissolution of synthetic condensates, subsequently allowing control over various cellular processes.

Selective separation and enrichment of phosphoproteins possess the distinct clinical and biological importance in the diagnosis, treatment, and management of several fatal human diseases. In this study, a facile synthesis of titanium(IV) ion–immobilized arsenate-modified poly(glycidyl methacrylate) microparticles (denoted as Ti4+-arsenate-PGMA-MPs) was developed for the efficient enrichment of intact phosphoproteins found in biologically complex protein samples. By virtue of the strong interaction between the titanium ions immobilized on the surface of Ti4+-arsenate-PGMA-MPs and phosphate groups of phosphoproteins, Ti4+-arsenate-PGMA-MPs had a high saturated adsorption capacity for phosphoproteins (901 mg/g for β-casein), which was much higher than that of non-phosphoproteins (73.5 mg/g for BSA). Ti4+-arsenate-PGMA-MPs were characterized by SEM, TEM, and FT-IR, and the average particle diameter was about 2.5 μm with good dispersibility. Besides, the application of Ti4+-arsenate-PGMA-MPs in real biological samples was investigated by SDS-PAGE analysis, and the results showed that Ti4+-arsenate-PGMA-MPs were able to enrich phosphoproteins efficiently.

Background This study analyzed the results of seven respiratory pathogen tests to investigate their epidemiological characteristics in children and provide clinical evidence for the prevention and control of acute respiratory infections (ARIs) in the pediatric population of Shanghai. Methods The test results for the seven pathogens (influenza A virus (FLUA), influenza B virus (FLUB), parainfluenza virus (PIV), adenovirus (ADV), respiratory syncytial virus (RSV), Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP)) were collected from 40,606 pediatric patients exhibiting clear ARI symptoms at Shanghai Children’s Medical Center, affiliated with Shanghai Jiao Tong University School of Medicine from January 2018 to December 2023 and retrospectively analyzed. Statistical analyses were conducted on positive detection rates, infection patterns, epidemic periods and variations based on sex and age. Results The overall positive detection rate for the seven respiratory pathogens was 22.57%. Compared with those in 2018, 2019 (pre-COVID-19) and 2023 (post-COVID-19), the rate significantly decreased during the pandemic period (2020–2022) ( P *<0.05), with mono-infections (mostly due to RSV, MP and PIV) being predominant. The epidemic periods of several pathogens shifted significantly after the pandemic. ADV (2.33%) and MP (14.52%) showed the highest positive detection rates among children aged 3 to < 6 years and 6 to < 12 years, respectively. Additionally, FLUA (1.46%) and FLUB (0.59%) exhibited the lowest rates in children aged 0 to < 3 years, while PIV (5.11%) and RSV (9.88%) showing the highest rates in the same age range. Finally, the positive detection rate of MP was significantly higher in girls (6.93%) than in boys (6.18%) ( P *<0.05). Conclusions The overall positive detection rate for the seven respiratory pathogens decreased significantly during the pandemic (2020–2022), with several pathogens showing notable shifts in their pre- and post-pandemic epidemic periods. MP, RSV and PIV were identified as the primary ARI-causing pathogens in children, and age- or sex-related differences also observed. This study enhances current understanding of the epidemiological characteristics of respiratory pathogen infections among children spanning the pre-, during, and post-COVID-19 periods, and provides critical insights for developing more effective prevention and control strategies in Pudong, Shanghai.