Sarcopenia profoundly impacts the quality of life and longevity in elderly populations. Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TRα). Emerging evidence suggests that decreased TRα expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TRα deficiency in sarcopenia are not fully understood. This study suggests that TRα may regulate mitochondrial calcium (Ca²⁺) transport across membranes by targeting the inositol 1,4,5-trisphosphate receptor 1 (IP3R1), as evidenced by ChIP-seq and RNA-seq analyses. Experiments using naturally aged mice, skeletal muscle-specific TRα knockout (SKT) mice, and C2C12 myoblasts were conducted to investigate this process further. Findings include increased IP3R1, mitochondria-associated endoplasmic reticulum membranes (MAM), and mitochondrial Ca²⁺ in aged skeletal muscle. Additionally, SKT mice exhibited smaller muscle fibres, increased IP3R1 and MAM, and mitochondrial dysfunction. ChIP-qPCR and TRα manipulation in C2C12 cells showed that TRα negatively regulates IP3R1 transcription. Moreover, TRα knockdown cells exhibited increased Ca²⁺ transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2-aminoethoxydiphenyl borate. Reintroduction of TRα improved IP3R1-mediated mitochondrial Ca²⁺ overload in aged cells. Our findings uncover a novel mechanism by which TRα deficiency induces mitochondrial Ca²⁺ overload through IP3R1-mediated Ca²⁺ transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TRα/IP3R1 pathway in MAM Ca²⁺ transfer presents a potential therapeutic target for sarcopenia.

Macrophages and bone marrow mesenchymal stem cells (BMSCs) share a close relationship within the osteoimmune microenvironment. During mechanically induced bone formation, macrophages respond to stimuli and regulate this microenvironment, influencing BMSCs' proliferation and differentiation. However, the underlying mechanisms remain incompletely understood. In our study, we employed a cellular tension system and found that mechanical tension altered mitochondrial dynamics in macrophages, leading to increased mitochondrial fission. Using a macrophage-BMSC direct co-culture system, we demonstrated that macrophages transferred mitochondria to BMSCs, a process enhanced by tension. This enhancement was associated with Drp1-mediated mitochondrial fission, as Drp1 knockdown in macrophages abolished the effect. Additionally, using in vitro co-culture and in vivo tibial injection models, we found that mitochondria-rich extracellular vesicles (Mito-EVs) secreted by mechanically stretched macrophages promoted BMSCs' osteogenesis and enhanced bone formation via the CD200 receptor (CD200R)-CD200 interaction. Our findings reveal a pivotal role for mitochondrial transfer in promoting osteogenesis during mechanotransduction, highlighting a novel mechanism of intercellular communication in bone biology.

Adeno-associated virus (AAV) has emerged as the predominant viral vector in clinical gene therapy. However, its widespread application confronts critical challenges, including pre-existing neutralising antibodies in 40%–80% of the population, species-dependent therapeutic discrepancies, and suboptimal tropism specificity. While current AAV capsid modification strategies (e.g., directed evolution and rational design) have advanced the field, their implementation has been hampered by incomplete mechanistic understanding and persistent translational roadblocks, necessitating the need for the discovery of novel AAV capsids. In this study, we systematically captured 1925 natural AAV variants from non-human primate (NHP) tissues by integrating multiple Polymerase Chain Reaction (PCR) primers and deep long-read sequencing technology, significantly expanding the natural capsid library by more than 20-fold and identifying 1274 representative AAV11 family variants. Based on the co-evolution analysis of these natural AAV11 variants, we designed the engineered variant AAV11.P5V6, which showed significantly enhanced transduction efficiency in human and NHP primary hepatocytes in vitro and achieved efficient targeting in a mouse central nervous system model. In addition, AAV11 and its variants maintain a strong antibody escape ability in human serum and immune animal models, exhibiting unique serological characteristics with almost no cross-neutralisation reaction with AAV8 and AAV9, confirming its low serum prevalence and immune evasion advantages. This study established a systematic framework of ‘natural discovery–evolutionary analysis–functional optimization’, providing a new paradigm for the development of next-generation AAV vectors with clinical-grade tissue specificity, low immunogenicity, and cross-species compatibility.

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.

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.

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.

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.

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^ExIII−/−) 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^ExIII−/− 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.

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.

Diabetes mellitus (DM) is a metabolic disorder marked by persistent hyperglycemia (HG), resulting from abnormalities in insulin secretion or insulin resistance. This condition represents a major public health concern since it causes multisystem complications, including microvascular diseases, macrovascular diseases, and neuropathy. Few effective therapies are currently available. Ferroptosis, an iron-dependent mode of regulated cell death triggered by lipid peroxidation (LPO), is intricately linked to the pathogenesis, progression, and complications of DM. It has been increasingly recognised as a key mechanism underlying peripheral insulin resistance and insulin deficiency resulting from β-cell dysfunction. In this study, we systematically summarised the primary regulatory mechanisms of ferroptosis and outlined current research advancements in mechanistic insights into its role in diabetic complications. Besides, we explored how inter-organelle interactions drive ferroptosis under diabetic conditions and play pathogenic effects in diabetes and its complications. Finally, we systematically reviewed the therapeutic drugs targeting ferroptosis from the perspectives of traditional Chinese medicine (TCM) and Western medicine, respectively. This interdisciplinary integrated overview may provide a theoretical basis for future clinical transformation.

Bioprinting with stem cells is an emerging technique for creating human tissues from scratch, transforming our understanding of biology and its biomedical applications. While significant attention has been paid to biochemical cues, mechanobiology is emerging as an equally important regulator in stem cell-based bioprinting, yet it has long been unexplored. Recent advances in elucidating mechanotransduction pathways underscore the need to comprehend bioink mechanics to bridge printability and stem cell fate regulation. This review emphasises the central role of mechanobiology in stem cell-based bioprinting: ensuring adequate printability while maintaining and programming stem cell functionality through biomechanical signals. We discuss how the mechanical properties of bioinks influence stem cell behaviour, with a focus on mechanosensitive stem cells, including pluripotent, mesenchymal, neural, hepatic and lung stem cells. Special attention is given to stem cell-based organoids and their associated mechanotransduction signalling pathways. We further identify four key mechanobiological requirements that define the relationship between print fidelity and the mechanical cues governing stem cell mechanosensing. We propose integrative strategies drawing from innovations in materials science and bioprinting to reframe mechanics as a tunable parameter rather than a constraint. Our roadmap aims to leverage bioink mechanics not only to facilitate biofabrication but also to guide stem cell fate and functional remodelling of engineered tissues for potential clinical applications.

C. Ya, L. Jin, J. Zhong, et al., “Dysregulation of Rho-Associated Coiled-Coil Protein Kinase1 Depletes Neural Stem Cell Pool and Impairs Hippocampal Neurogenesis After Traumatic Brain Injury,” Cell Proliferation 50, no. 2 (2025 Aug 1): e70093, https://doi.org/10.1111/cpr.70093.

In Figure 1D, the image labelled ‘Day 14’ was incorrectly duplicated from ‘Day 28’.

The corrected Figure is reproduced below:

We apologise for this error.