T. Liu, X. Zhang, K. Sha, X. Liu, L. Zhang and B. Wang, "miR-709 Up-Regulated in Hepatocellular Carcinoma, Promotes Proliferation and Invasion by Targeting GPC5," Cell Proliferation 48, no. 3 (2015): 330-337, https://doi.org/10.1111/cpr.12181. The above article, published online on 27 March 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Qi Zhou; and John Wiley & Sons Ltd. The retraction has been agreed upon following the identification of duplicated elements between Figures 5c and 7c, which were reported to represent different experimental conditions. The authors provided some supporting data; however, it was insufficient to fully address the concerns. As a result, the editors have lost confidence in the reliability of the results. The authors did not respond when asked to agree to the final wording of the retraction.

Genomic imprinting, an epigenetic process resulting in parent-specific gene expression, is essential for normal development and growth. Disruption of imprinting leads to various developmental disorders and cancers, yet our understanding of the full repertoire of imprinted genes in humans remains incomplete. Here, we utilised androgenetic, parthenogenetic and biparental human embryonic stem cells and their neural derivatives to identify novel imprinted genes by analysing their methylome and transcriptome profiles. Our analysis revealed 12 novel putative imprinted genes distributed across four distinct loci, with six of them clustered in an uncharacterised imprinted region on chromosome 19. We identified potential imprinting control regions regulating this novel cluster, suggesting a coordinated regulatory mechanism. Notably, these imprinted genes are enriched in cancer-related pathways, with several showing isoform-specific imprinting patterns. Our analysis also revealed consistent DNA methylation aberrations in pluripotent stem cells at specific imprinted loci, highlighting potential epigenetic instability during culturing. These findings contribute to our understanding of genomic imprinting regulation in human development and highlight potential genomic regions for further investigation of imprinting-related disorders.

A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.

Mitochondrial quality control (MQC) impairment plays a central role in driving the pathogenesis of metabolism-associated steatotic liver disease (MASLD). Specifically, this is manifested as reduced mitophagy; increased mitochondrial fission and decreased fusion; and impaired mitochondrial biogenesis. Key pathological mechanisms of MASLD, such as hepatocyte apoptosis, pyroptosis, and ferroptosis, are activated under the influence of factors including free fatty acids (FFAs), oxidative stress, NLRP3 inflammasome activation, and gut microbiota imbalance. Meanwhile, the letter also lists novel potential therapeutic strategies targeting these pathways, including autophagy enhancers, mitochondrial dynamics regulators, biogenesis promoters, and ferroptosis inhibitors.

Spinal cord injury (SCI) is a devastating condition with limited therapeutic options. Although neural stem cell (NSC) transplantation shows regenerative potential, its efficacy is constrained by the hostile post-injury microenvironment. Here, we employed untargeted metabolomics to investigate metabolic reprogramming induced by NSC-loaded multichannel collagen scaffolds in a rat SCI model. NSC transplantation significantly enhanced functional recovery and structural remodelling, concomitant with elevated neurogenesis and attenuated gliosis. Metabolomic profiling identified lysophosphatidylcholine 18:0 (LPC18:0) as a key NSC-derived metabolite. Mechanistically, LPC18:0 promoted the differentiation of endogenous NSCs into neurons via the GPR55/AKT/GSK3β signalling axis, as validated by receptor-specific inhibition. In vivo administration of LPC18:0 improved motor function, axonal regeneration and recruitment of immature neurons. These findings reveal a novel metabolic mechanism underlying NSC-based therapy, positioning LPC18:0/GPR55/AKT/GSK3β signalling as a therapeutic target for SCI recovery.

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technologies, with the underlying molecular mechanisms still largely unknown. Here, we conducted proteomic profiling and analysed publicly available single-cell RNA sequencing data, revealing a marked decrease in lactate dehydrogenase A (LDHA) expression in RIF cases. While traditionally considered a metabolic byproduct, it is now recognised to play a role in signalling and epigenetic regulation. Utilising human endometrial organoids, we demonstrated that lactate enhances human endometrial receptivity by promoting epithelial-mesenchymal transition (EMT) and upregulating histone H3 lysine 18 lactylation (H3K18la). Further multi-omics analyses identified solute carrier family 7 member 11 (SLC7A11) as an H3K18la-regulated target. Functional assays confirmed that lactate-induced H3K18la upregulates SLC7A11, thereby driving EMT and cellular migration. Notably, using a blastoid-endometrial cell implantation model, we demonstrated that SLC7A11 promotes both blastoid adhesion and expansion, highlighting its critical role in embryo-endometrial interactions. Collectively, leveraging multiple organoid systems, including endometrial organoids and blastoid-endometrial cell implantation models, our findings reveal a novel lactate-H3K18la-SLC7A11 axis that orchestrates endometrial epithelial plasticity and receptivity. In addition, this study established a robust methodological framework for investigating implantation mechanisms.

Obstructive sleep apnea (OSA) is strongly associated with an increased risk of hypertension; however, the molecular mechanisms linking these two conditions remain incompletely understood. In this study, we identified phosphodiesterase 4B (PDE4B) as a key mediator in the development of OSA-related hypertension. Using integrated bioinformatics analysis and experimental validation, we found that PDE4B expression was significantly elevated in both cell and animal models of OSA combined with pulmonary hypertension. Functional studies demonstrated that PDE4B promotes pulmonary artery smooth muscle cell (PASMC) proliferation and migration, contributing to vascular remodelling. Mechanistically, we uncovered that lactate accumulation under hypoxic conditions induces histone lactylation at the PDE4B promoter, enhancing its transcriptional activity. Furthermore, PDE4B was shown to regulate the phosphorylation and nuclear translocation of FUS, which binds to the angiotensinogen (AGT) promoter and enhances AGT expression, thereby promoting pulmonary hypertension. These findings reveal a novel PDE4B-FUS-AGT signalling axis driven by epigenetic modifications in OSA-induced hypertension, offering potential therapeutic targets for patients with this comorbidity.

Compared to classical drug screening, single-cell screening not only significantly enhances throughput but also provides richer transcriptional response information. In this study, we employed the high-throughput and high-sensitive single-nucleus sequencing platform, snHH-seq, to screen clinical drug combinations with anti-hepatocellular carcinoma (HCC) activity. Single-cell transcriptomics analysis revealed that the HY combination (HHT and YM155) exhibited the strongest suppression of tumour cell proliferation, a finding validated by both in vitro and in vivo functional assays. Further investigation suggested that HY triggers ferroptosis, as evidenced by rescue from cell death upon co-treatment with the ferroptosis inhibitor Fer-1. Subcluster analysis identified distinct tumour cell subclusters' responses to HY treatment. A gene regulatory network analysis highlighted JUN as a key regulator mediating proliferation inhibition, primarily active in the apoptotic cell subcluster. These findings illustrate how integrating high-throughput screening with mechanistic dissection can accelerate the discovery of targeted drug combination therapies, and offer a blueprint for precise interventions using pathway vulnerabilities and cellular heterogeneity in HCC.

Decreased sialic acid increases the adhesion of RBC membranes to immunoglobulins leading to an increased erythrocyte sedimentation rate (ESR). The increase in reactive oxygen species (ROS) damages the sialic acid glycosyl chains on the surface of RBC membrane proteins, causing the membrane proteins to be overexposed to the plasma environment due to the loss of sialic acid coverage. Immunoglobulins in plasma adhere to RBC membrane Band3 extracellularly exposed peptides through intermolecular interactions. The reduction of sialic acid causes a weakening of the RBC membrane negative charge barrier and the adhesion of immunoglobulins further destabilises the suspension of RBCs, resulting in a rapid addition of ESR to multiple myeloma.

Circadian rhythm is an essential biological process that synchronises physiological activities with environmental light/dark cycles. However, its regulatory mechanisms in tooth development remain incompletely understood. Here, we investigated the role of the p75 neurotrophin receptor (p75NTR) in circadian rhythm regulation and daily mineralization during tooth development using immunofluorescence, circadian rhythm tracking, and genetic models. Spatiotemporal analysis of rat dental germs revealed that oscillatory expression patterns of p75NTR closely aligned with clock genes (Bmal1, Clock, Per1, Per2), mineralization-related factors, and odontogenesis-related factors. p75NTR knockout mice (p75NTR) exhibited reduced body weight, lower melatonin levels, delayed incisor eruption, decreased daily mineralization width, and downregulation of core clock genes. Mechanistically, p75NTR overexpression in immortalised stem cells from the dental apical papilla (iSCAPs) upregulated casein kinase 2 (CK2) expression, enhanced PER2 phosphorylation, and promoted nuclear p-PER2 accumulation, while CK2 inhibition partially reversed these effects. In vivo, CK2 inhibition via quinalizarin exacerbated incisor eruption defects in p75NTR mice. These findings demonstrate that p75NTR regulates circadian-driven mineralization and tooth morphogenesis, probably via the CK2/PER2 pathway, providing critical insight into the interplay between the circadian rhythm and dental development.

Periodontal regeneration requires coupled angiogenesis and osteogenesis, while current strategies to promote angiogenesis face limitations such as poor cytokine stability and safety concerns. Nanosilicates (nSi), as bioactive nanomaterials with potent properties, show promise for enhancing bone regeneration via osteogenic pathways. However, their pro-angiogenic potential and precise mechanisms, particularly within the periodontal microenvironment, remain poorly understood. This study addresses this knowledge void by introducing nSi into rat periodontal defects, revealing significantly enhanced vascular network formation and bone repair in vivo. Crucially, through intervention in relevant signalling pathways, this research provides the first evidence for the molecular mechanism underlying nSi-induced angiogenesis in endothelial cells. We demonstrate that nSi regulate microtubule homeostasis via the MAPK-mediated MAP4 signalling pathway, facilitating STAT3 nuclear translocation and ultimately promoting angiogenic differentiation. This mechanistic elucidation fills a critical gap in understanding the nSi-cytoskeleton-transcriptional regulation axis. These findings offer fundamental insights to guide the rational design and optimisation of nSi-based biomaterial systems for vascularised periodontal regeneration.

Luteolin alleviates DSS-induced ulcerative colitis in mice by targeting the NLRP3 inflammasome, as it shows no effect in NLRP3 mice. It inhibits NLRP3 activation and IL-1β secretion in macrophages by reducing ROS, mtROS and calcium levels via AMPK binding and signalling. Metabolomic changes suggest lipid metabolism involvement. Luteolin represents a promising NLRP3-targeted therapeutic candidate for UC.

Open skin wounds caused by burns, trauma, or underlying diseases impose substantial clinical challenges and significantly compromise patients' quality of life due to their complex management and high risk of scarring. In this study, we explore the therapeutic potential of apoptotic vesicles derived from interleukin-10-treated fibroblasts (IL10_ApoEVs) in promoting cutaneous wound healing and mitigating fibrotic scar formation. Our results demonstrate that IL10_ApoEVs enhance mitochondrial function and oxidative phosphorylation (OXPHOS), while concurrently suppressing glycolytic activity in fibroblasts. Importantly, IL10_ApoEVs markedly inhibit the Hedgehog signalling pathway, a key driver of fibrogenesis in various tissues, as evidenced by the downregulation of Shh and Gli1 expression. This modulation leads to attenuated aberrant extracellular matrix (ECM) deposition and promotes a favourable shift in collagen composition. This is characterized by increased type III collagen and reduced type I collagen, which is indicative of more elastic and functionally integrated tissue remodelling. These findings suggest that IL10_ApoEVs contribute to a regenerative microenvironment that supports scarless or minimally fibrotic healing. Collectively, our work highlights the promising application of IL10_ApoEVs in regenerative medicine and provides mechanistic insights into their dual role in metabolic reprogramming and antifibrotic signalling modulation during tissue repair.

Pulmonary vascular endothelial cells (VECs) are essential for the normal function of the lung, through maintaining vascular barrier integrity, regulating blood flow, and participating in inflammatory responses to safeguard oxygen exchange and physiological homeostasis. The occurrence and development of various pulmonary diseases all take the injury of pulmonary VECs as an important pathological hub, which directly affects the therapeutic effect and prognosis recovery of patients. The injury mechanisms of pulmonary VECs present multi-dimensional network characteristics, involving inflammation and oxidative stress, genetic factors, cellular senescence, metabolic abnormalities, and immune dysregulation. Due to the unique physiological structure of the lungs, traditional drugs often encounter significant challenges in clinical application such as insufficient targeting, low bioavailability, and systemic side effects. In order to overcome the existing treatment bottlenecks, it is crucial to implement an in-depth analysis of the molecular mechanism of pulmonary VECs injury. This review systematically explores the mechanisms of pulmonary VECs injury, evaluates novel therapeutic strategies targeting pulmonary VECs' dysfunction, and discusses the challenges and future prospects of clinical translation. The goal is to shift pulmonary diseases treatment from symptom management to precise molecular intervention.

Regeneration of the central nervous system (CNS) is a complex and tightly regulated process, yet the precise molecular players and transcriptional regulators involved remain incompletely understood. Here, we identify Host Cell Factor-1 (Hcfc1), a transcriptional co-regulator, and O-GlcNAc transferase (Ogt), which cleaves and O-GlcNAcylates HCF-1, as crucial regulators of zebrafish brain and retinal regeneration. We uncover their interplay with the Hippo/Yap signalling pathway, a well-known regulator of tissue growth and repair. Knockdown of hcfc1a/b or Ogt activity inhibition disrupts regeneration and reduces Yap levels, while Yap inhibition alone also impairs regeneration. Strikingly, overexpression of constitutively active Yap5SA rescues proliferation defects caused by Hcfc1 depletion and Ogt inhibition in retinal regeneration. Further, yap1 knockdown reduces hcfc1a/b levels, suggesting potential feedback regulation. These findings reveal a previously unrecognised regulatory axis involving Hcfc1, Ogt, and the Hippo/Yap pathway, which governs CNS regeneration. Targeting this pathway could offer a strategy for enhancing CNS regeneration.

Sleep deprivation (SD) is a common issue among pregnant women. Maternal SD led to adverse effects on offspring health such as cognitive impairment through dysregulated metabolic pathways. However, it remains unknown whether maternal SD increases the offspring's susceptibility to nonalcoholic steatohepatitis (NASH) development. Here, we induced maternal SD during pregnancy and observed that maternal SD during pregnancy promoted the development of diet-induced NASH in offspring of both sexes in adulthood, with exacerbation of liver weight gain, hepatic steatosis, fibrosis, and hepatic dysfunction. The primary hepatocytes isolated from SD offspring were also more susceptible to palmitate acid-induced lipotoxic injury. Mechanistically, the detrimental effects of maternal SD were associated with augmented activation of inflammatory and apoptosis pathways in offspring liver tissues, which were attributed to upregulation of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). The melatonin signalling is reported to be pivotally affected by sleep disturbance both at the circulation and the placenta, and our further analysis revealed that melatonin supplementation during maternal SD normalised NR4A3 expression in offspring liver and alleviated the increased steatohepatitis susceptibility in offspring. Taken together, these results suggest that maternal SD during pregnancy predisposes offspring to NASH development in adulthood via an NR4A3-dependent mechanism, and maternal melatonin supplementation may hold promise for improving liver health in the offspring.

Cellular geometry is tightly associated with the function of a cell. During tumour progression, cancer cells undergo changes in phenotypes and biological behaviour with deformations in cellular morphology. However, whether the morphological diversity of cancer cells correlates with the cellular phenotype, and the underlying mechanism of morphology-related function in cancer cells is still unclear. Here, we simplified the cellular morphology by clustering cancer cells into three categories based on two-dimensional cellular morphological features. The silence of caveolin-1 (Cav-1), the primary constituent of membrane caveolae, reproduced the morphological evolutionary behaviour of cancer cells, which is similar to the epithelial-mesenchymal transition process. The attenuation of dorsal stress fibres, the assembly of focal adhesions and the disorder of transverse arc fibres and their regulatory signals are demonstrated as the main morphological evolutionary tools of cancer cells. Moreover, a modified vertex model theoretically reconfirmed the evolutionary process of cellular morphology. Small GTPases and focal adhesion kinase signalling were implicated in Cav-1 knockdown-induced cytoskeletal remodelling and focal adhesion assembly. Both in vitro and in vivo studies have demonstrated that Cav-1-dependent morphological changes are closely associated with the self-renewal capacity of breast cancer cells. Overall, our work highlights new insight into the morphological diversity and the correlation between cellular shape and phenotype of cancer cells, and provides evidence that Cav-1 could affect cancer cell properties such as self-renewal capacity through maintaining the morphological stability.

The malignant transformation of cancer cells is underpinned by the dysregulation of essential cellular processes, including genome stability maintenance, DNA repair, transcriptional control and signal transduction. These processes are not randomly distributed but are spatiotemporally coordinated through dynamic molecular assemblies. Recent advances have highlighted the pivotal role of biomolecular condensates, membraneless compartments formed via liquid-liquid phase separation (LLPS), in compartmentalising and regulating these key functions. LLPS enables the concentration and organisation of proteins and nucleic acids, creating distinct biochemical environments that facilitate cellular decision-making. Importantly, aberrant phase separation has been increasingly implicated in the acquisition of cancer hallmarks, such as sustained proliferative signalling, resistance to cell death and immune evasion. In this review, we summarise the physicochemical principles of LLPS, examine its emerging roles in oncogenic transformation and discuss the therapeutic potential of targeting phase separation in cancer. Our findings highlight LLPS as a novel and versatile regulatory layer in tumour biology and an emerging frontier in precision oncology.

The normal growth and development of skeletal muscle are crucial for the proper function of organisms. During myoblast development, cell death is a fundamental physiological process, and skeletal muscle damage involves various types of cell death, including ferroptosis. However, ferroptosis-related biomarkers in skeletal muscle damage remain unclear. This study aimed to investigate the mechanisms by which lipocalin-2 (LCN2), a key protein of iron metabolism, regulates skeletal muscle regeneration post damage by mediating ferroptosis. When the gastrocnemius muscle (GAS) of mice is acutely injured, LCN2 is significantly upregulated early in the injury. In vitro, LCN2 participates in the inhibition of proliferation and differentiation of C2C12 cells via erastin-induced ferroptosis. Transcriptomic analysis after the overexpression of LCN2 revealed that the one with the most significant difference among all of the differentially expressed genes (DEGs) was aconitate decarboxylase 1 (Acod1). The inhibition of myogenic factors' expression by LCN2 was associated with the activation of the ferroptosis signalling pathway, partly attributed to the mitochondrial dysfunction. The ACOD1 inhibitor attenuated mitochondria-associated ferroptosis induced by LCN2 and alleviated the inhibitory effect of LCN2 on cell viability. These findings highlight the therapeutic potential of targeting the LCN2-ACOD1 signalling to promote myogenesis, providing promising strategies for facilitating the regeneration of skeletal muscle after injury and the treatment of muscle-related diseases.

Advancements in the generation of human pluripotent stem cell-derived natural killer (PSC-NK) cells have attracted considerable attention within the biomedical research community, offering a promising off-the-shelf technique for universal immune therapy. However, this technique is associated with certain ethical, safety, and regulatory challenges, including ensuring genomic stability, preventing contamination and adhering to rigorous ethical standards for cell sourcing and obtaining informed consent. Addressing these challenges would require robust quality control, transparent data-sharing practices, and cross-border collaboration to ensure alignment with ethical and scientific standards. Future development must therefore focus on patient safety, data privacy and equitable access within a comprehensive ethical framework. These measures are crucial for maintaining public trust in and enabling the responsible clinical integration of PSC-NK therapies, thereby supporting their advancement while maintaining a balance between innovation and societal and ethical considerations.