Periapical periodontitis is one of the most common inflammatory bone destructive diseases. Epidemiological evidence suggests that hypoxia exposure, such as that resulting from high-altitude exposure or sleep apnea syndro...Periapical periodontitis is one of the most common inflammatory bone destructive diseases. Epidemiological evidence suggests that hypoxia exposure, such as that resulting from high-altitude exposure or sleep apnea syndrome, may be a significant risk factor that exacerbates the disease process. However, its specific role and the underlying molecular mechanisms remain unclear. In this study, we established a mouse model of periapical periodontitis under conditions of chronic hypoxia to evaluate its impact on pathological bone loss using micro-computed tomography, histological staining, and serum cytokine analysis. Furthermore, we explored the potential molecular regulatory mechanisms using in vitro osteoclast differentiation models, adeno-associated virus-mediated in vivo gene knockdown, and cleavage under targets and tagmentation (CUT&Tag) sequencing. Our study revealed that hypoxia exposure significantly aggravated alveolar bone resorption, osteoclast activation, and systemic inflammation in the mouse model of periapical periodontitis compared to normoxia. At the molecular level, hypoxia-inducible factor-1α (HIF-1α) showed a rapid but transient increase under hypoxia, whereas HIF-2α displayed a progressive and sustained elevation throughout osteoclast differentiation. These dynamics indicate that HIF-2α plays a more prominent role than HIF-1α in mediating the hypoxia-accelerated osteoclastogenic response. In vivo, local knockdown of HIF-2α in the periapical region markedly attenuated bone destruction exacerbated by hypoxia exposure. Further mechanistic investigation, combining CUT&Tag sequencing and functional validation experiments, revealed that HIF-2α mediates its pro-osteoclastogenic function by directly binding to the promoter region of the calmodulin-dependent protein kinase IV (Camk4) gene and activating its transcription. This study unveils that hypoxia exposure, acting as a critical environmental risk factor, functions as a 'synergistic amplifier' to enhance pathological osteoclastic responses in periapical periodontitis through the HIF-2α-CAMK4 regulatory axis. The findings deepen our understanding of periapical periodontitis and suggest that targeting HIF-2α or downstream pathways may be an adjunctive therapeutic strategy for hypoxia-associated inflammatory bone loss.
Liu K, Zhang W, Jiang X
… +14 more, Chen J, Zhu L, Zhang Z, Gu J, Guo L, Ao L, Chen Q, Sun L, Hu Y, Wang X, Liu Y, Cao J, Han F, Liu J
Cell Prolif
· 2026 Jun · PMID 41467312
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Meiosis, a specialised form of cell division, is essential for sexual reproduction, which requires the proper formation of synaptonemal complex (SC) and homologous recombination (HR). However, the regulatory mechanisms u...Meiosis, a specialised form of cell division, is essential for sexual reproduction, which requires the proper formation of synaptonemal complex (SC) and homologous recombination (HR). However, the regulatory mechanisms underlying these processes remain incompletely understood. Here, we demonstrate that SOX30 is a key transcriptional regulator of male meiotic synapsis and recombination. In Sox30-knockout mice, zygotene spermatocytes accumulate with synapsis defects. SOX30 deficiency disrupts the SC central element components SYCE1, SYCE2, and TEX12 distribution. Furthermore, disrupted γ-H2AX distribution reveals impaired DNA double-strand break repair and the persistence of recombination proteins RAD51 and RPA2 in late spermatocytes confirms defective homologous recombination repair (HRR) which results in reduced crossover formation in Sox30-knockout mice spermatocytes. Mechanistically, SOX30 directly binds to SYCE1/SYCE2 promoters to modulate their transcription, thereby regulating SC assembly and HRR. Restoring SOX30 expression effectively rescues meiotic defects. Importantly, transcriptome co-expression analysis in non-obstructive azoospermia (NOA) testes identifies SOX30 as a central regulator of NOA transcriptional networks. Collectively, these findings underscore SOX30's crucial role in meiotic synapsis and recombination, highlighting its therapeutic potential for NOA.
Xu J, Zhang X, Ma A
… +21 more, Hao J, Li T, Fu B, Ma L, Liu Y, Xiang P, Qian K, Han X, Li Y, Zhu L, Li Q, Wei Q, Wu T, Wang L, Cao J, Li K, Zhao H, Niu S, Hu B, Zhao T, Chen H
Cell Prolif
· 2026 Feb · PMID 41467306
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Cell Prolif
· 2026 Mar · PMID 41457765
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Atherosclerosis remains a significant global health challenge, arising from the complex interactions among dysregulated lipid metabolism, chronic inflammation and immune activation. Ferroptosis, marked by lipid peroxide...Atherosclerosis remains a significant global health challenge, arising from the complex interactions among dysregulated lipid metabolism, chronic inflammation and immune activation. Ferroptosis, marked by lipid peroxide buildup dependent on iron, is gaining recognition as a modulator of macrophage activity in atherosclerosis. Macrophages are the pivotal orchestrators of chronic inflammation and atherosclerotic plaque formation. The marked heterogeneity and plasticity of macrophages within plaques dynamically shape the local microenvironment, contributing to phenomena such as lipid overload, cytokine overactivation, hypoxia, and programmed cell death. This review examines how dysregulated iron handling, lipid metabolism, and redox imbalances synergise to induce macrophage ferroptosis in atherosclerosis. Moreover, ferroptosis contributes to the development and progression of atherosclerosis by causing dysfunction in vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and macrophages, thereby promoting plaque formation and instability. Furthermore, macrophages are intricately linked to ferroptosis, with this iron-dependent cell death enhancing oxidative stress and inflammatory pathways. Macrophage ferroptosis drives plaque progression and destabilisation, ultimately heightening the risk of rupture and cardiovascular events. By inhibiting macrophage ferroptosis, it may be possible to reduce oxidative stress and inflammation, stabilise atherosclerotic plaques, and ultimately lower the risk of cardiovascular events. This review highlights the therapeutic potential of targeting macrophage ferroptosis for the treatment of atherosclerosis.
Zhang J, Zhao Y, Deng J
… +4 more, Qu S, Zhou Y, Zhao Q, Zhang Y
Cell Prolif
· 2026 Jun · PMID 41431329
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Periodontitis is a chronic inflammatory disease driven by a dysregulated host immune response, in which macrophage-mediated inflammation shifts from protective to pathological. While monocyte-derived macrophages (MDMs) a...Periodontitis is a chronic inflammatory disease driven by a dysregulated host immune response, in which macrophage-mediated inflammation shifts from protective to pathological. While monocyte-derived macrophages (MDMs) are known to adopt a destructive, M1-like pro-inflammatory phenotype, the mechanisms that enable this 'runaway' polarisation by bypassing endogenous negative feedback remain elusive. Here, we identify alternative polyadenylation (APA) as a critical post-transcriptional mechanism driven by pathogens to disrupt macrophage immune control. Integrating single cell RNA sequencing with Sierra APA analysis of human gingival tissues, we uncovered a global shift toward proximal poly(A) site (PAS) usage, indicative of 3'UTR shortening, specifically within the pro-inflammatory MDM subset. This APA remodelling preferentially affected genes essential for cytokine production and inflammatory signalling. In vitro, the keystone pathogen Porphyromonas gingivalis similarly induced widespread 3'UTR shortening in macrophages. This shortening systematically eliminated inhibitory miRNA-binding sites, thereby derepressing pro-inflammatory transcripts. Mechanistically, using Selenok as a representative example, we demonstrate that P. gingivalis induced 3'UTR shortening selectively abolishes repression by miR-320-3p, a 'brake' miRNA upregulated in periodontitis, whose binding site is excised by the proximal APA event. Collectively, these findings reveal APA remodelling as a key pathogenic strategy that enables pro-inflammatory macrophages to escape miRNA-mediated suppression, leading to an uncontrolled M1-like state. This 'disruption' of the post-transcriptional braking system provides a new mechanistic rationale for the persistent, destructive inflammation in periodontitis.
Zhao C, Qiu Y, Wang X
… +7 more, Wang M, Liu L, Zhao X, Gao Z, Shao R, Xia G, Zhao W
Cell Prolif
· 2026 Mar · PMID 41419319
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LMPt enters the cell mainly through caveolin-mediated endocytosis, and then fuses with endosomes and lysosomes to deliver MPt to mitochondria and the endoplasmic reticulum to induce mitophagy based on the fusion of lysos...LMPt enters the cell mainly through caveolin-mediated endocytosis, and then fuses with endosomes and lysosomes to deliver MPt to mitochondria and the endoplasmic reticulum to induce mitophagy based on the fusion of lysosomes and mitochondria, and endoplasmic reticulum stress and subsequent apoptosis via the Bip-PERK-eIF2α-ATF4 axis to exert an anti-breast cancer effect.
Wang J, Zhang Y, Wu L
… +8 more, Xie H, Yang G, Zhang Y, Huang C, Chou S, Li X, Liu Z, Wang J
Cell Prolif
· 2026 Jun · PMID 41403070
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The transcriptional effector of the Hippo signalling pathway, YAP, regulates the first lineage specification in mouse preimplantation embryos. However, how YAP undergoes dephosphorylation specifically in the trophectoder...The transcriptional effector of the Hippo signalling pathway, YAP, regulates the first lineage specification in mouse preimplantation embryos. However, how YAP undergoes dephosphorylation specifically in the trophectoderm (TE) but not in the inner cell mass (ICM) remains unresolved. Here, we discovered that the serine/threonine phosphatase PPP1CC exhibits uniform distribution prior to blastocyst formation but becomes specifically localised to the TE during the blastocyst stage. Through mediating YAP dephosphorylation in the outer cells of mouse morula, PPP1CC facilitates YAP nuclear translocation, thereby ultimately driving TE lineage specification. Importantly, the spatially restricted localisation of PPP1CC in TE is achieved via its interaction with the long non-coding RNA GAS5, which localises to the subcortical region throughout early mouse embryonic development. Knockdown of GAS5 phenocopies PPP1CC deficiency, causing developmental arrest at the morula stage accompanied by impaired YAP dephosphorylation in outer cells. Moreover, overexpression of GAS5 in one blastomere of the 2-cell stage biases its descendants predominantly towards the TE fate. In summary, our study identifies the GAS5-PPP1CC-YAP axis as a central regulator of first lineage specification during mouse preimplantation development, highlighting its critical role in reversible phosphorylation during early embryogenesis.
Cell Prolif
· 2026 Jan · PMID 41330873
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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...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.
Cell Prolif
· 2026 Jun · PMID 41328039
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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 o...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.
Bian S, Cui J, Zhang X
… +14 more, Bai C, Tan Y, Hao Z, Bu X, Qu C, Sun L, Lin L, Wang Q, Li Z, Huang X, Liu H, Wang R, Li Y, Wang H
Cell Prolif
· 2026 Mar · PMID 41308657
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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 glycosy...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.
Jiang M, Chen H, Wen G
… +10 more, Mei Y, Zhou W, Xu B, Zhang T, Li G, Wu J, Han X, Fu X, Guo G, Wang J
Cell Prolif
· 2026 Jun · PMID 41308634
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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 hig...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.
Yang L, Ni Q, He Y
… +10 more, Liu S, Gan L, Dai A, Hu Y, Liu Q, Yang X, Li J, Tao Y, Li Y, Xu M
Cell Prolif
· 2026 May · PMID 41243803
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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 pho...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.
Dong L, Sun X, An S
… +7 more, Xiang J, Hu L, Yao D, Chang J, Jia R, Yang Y, Wang S
Cell Prolif
· 2026 Jun · PMID 41242872
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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 pu...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.
Chen D, Liu S, Tu LY
… +9 more, Yang MM, Xu CW, Jiang Y, Yang H, Tai CX, Wang YN, Xie YY, Shen PP, Wang B
Cell Prolif
· 2026 Jun · PMID 41242751
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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 m...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.
Fu W, Wang J, Lu N
… +6 more, Guo Z, Ong SB, Gao Y, Zhou H, Chang X, Meng M
Cell Prolif
· 2026 Feb · PMID 41207882
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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 m...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.
Zhang X, Dong X, Zhang X
… +7 more, Yuan S, Zhang Q, Guo Z, Yang X, Wang Q, Yang T, Huang D
Cell Prolif
· 2026 Jan · PMID 41189301
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A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.A mechanistic network of ovarian aging, highlighting mitochondrial dysfunction as a central hub interconnected with genetic, metabolic, and inflammatory pathways.
Cell Prolif
· 2026 May · PMID 41187737
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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 bioa...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.
Zhao M, Yuan H, Wang D
… +6 more, Li M, Xie B, Zou X, Lu M, Qiu Y, Song J
Cell Prolif
· 2026 May · PMID 41185464
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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....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.
Li S, Duan H, Yang L
… +12 more, Jiang L, Bian H, Jiang Y, Zhang Y, Yan W, Yang Q, Li T, Qin X, Liu ZY, Sun N, Yang KF, Liu Y
Cell Prolif
· 2026 May · PMID 41164943
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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, wheth...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.