Cell Prolif
· 2025 Oct · PMID 40855640
·
Full text
Roles of primary cilia and the signals they transmit in the development of myocardial fibrogenesis, cardiac hypertrophy, and atrial fibrillation. Left, Fibroblasts can differentiate into myofibroblasts in response to TGF...Roles of primary cilia and the signals they transmit in the development of myocardial fibrogenesis, cardiac hypertrophy, and atrial fibrillation. Left, Fibroblasts can differentiate into myofibroblasts in response to TGF-β1. TGF-β1 stimulation via both paracrine action in the heart and exogenous action on primary cultured fibroblasts activated the phosphorylation of SMAD3 and the transcription of the fibronectin and collagen type I and III genes. Middle, Vesicles derived from cilia are secreted at an accelerated rate under fluid shear stress. Blockage of ciliary protein, which is required for cELV generation with shRNA, led to blunted cELV secretion and left ventricular hypertrophy. Right, under pathological conditions such as atrial fibrillation (AF), fibroblasts exhibit increased proliferation and differentiation into α-smooth muscle Actin (αSMA)-expressing myofibroblasts. This disrupts ECM dynamics, ultimately leading to interstitial fibrosis within the atria. AF patients presented increased HDAC6 activity and reduced levels of acetylated α-tubulin in left atrial tissues. HDAC6 activity is activated by the interaction of aurora kinase A (AURKA), and neural precursor cells express developmentally downregulated protein 9 (NEDD9) via phosphorylation. LiCl prompts the reversion of αSMA-positive myofibroblasts into αSMA-negative fibroblasts.
Shi R, Zhang Y, Chen G
… +5 more, Zhang J, Liu J, Zhu H, Sun M, Duan Y
Cell Prolif
· 2026 May · PMID 40851314
·
Full text
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 skelet...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 (Ca) 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 Ca 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 Ca transfer in MAM and mitochondrial dysfunction, which was ameliorated by the IP3R1 inhibitor 2-aminoethoxydiphenyl borate. Reintroduction of TRα improved IP3R1-mediated mitochondrial Ca overload in aged cells. Our findings uncover a novel mechanism by which TRα deficiency induces mitochondrial Ca overload through IP3R1-mediated Ca transfer in MAM, exacerbating skeletal muscle atrophy during ageing. The TRα/IP3R1 pathway in MAM Ca transfer presents a potential therapeutic target for sarcopenia.
Xu M, Wang Q, Wang F
… +10 more, Kang L, Ma H, Li M, Hao Z, Li Z, Liu J, Huang X, Liu H, Wei S, Yang H
Cell Prolif
· 2025 Dec · PMID 40797362
·
Full text
PE is a life-threatening pregnancy disorder that can lead to adverse events for both the fetus and the mother. Autophagy is a cellular process involved in cellular renovation and maintaining homeostasis. There is a growi...PE is a life-threatening pregnancy disorder that can lead to adverse events for both the fetus and the mother. Autophagy is a cellular process involved in cellular renovation and maintaining homeostasis. There is a growing body of evidence suggesting that autophagy in trophoblasts plays a significant role in the development and pathogenesis of PE. However, the exact mechanisms are not yet fully understood. This article provides an overview of recent evidence regarding the role of autophagy in trophoblast invasion, vascular remodelling, inflammation, immune response, and maternal factors in the context of PE. It is believed that impaired or excessive autophagy can contribute to placental ischaemia and hypoxia, thereby exacerbating PE progression. Therefore, understanding the molecular mechanisms that regulate autophagy in PE is crucial for the development of targeted therapeutic interventions in the future.
Cell Prolif
· 2026 Jan · PMID 40781923
·
Full text
Piezo2, a mechanically activated ion channel, serves as the key molecular transducer for touch, proprioception and visceral sensation. These mechanosensation processes, where mechanical forces are converted into electroc...Piezo2, a mechanically activated ion channel, serves as the key molecular transducer for touch, proprioception and visceral sensation. These mechanosensation processes, where mechanical forces are converted into electrochemical signals, are essential for sensory perception, interoception and systemic homeostasis. Critically, Piezo2 channels are fundamental to diverse physiological functions, such as skeletal growth, respiratory development and inter-organ homeostasis. Despite its established role in sensory neurons and specialised mechanotransducers, the molecular intricacy of Piezo2-mediated signalling and its pathophysiological relevance remain incompletely understood. This review highlights key evidence from recent studies employing advanced technologies supporting the potential of Piezo2 channels as vital mechanosensor that regulate mechanotransduction cascades in physiological systems, demonstrating their potential as drug targets for the development of therapeutic agents.
Luo J, Chen L, Zhang X
… +3 more, Su Q, Zhou X, Lian Q
Cell Prolif
· 2026 Mar · PMID 40767000
·
Full text
Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. How...Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).
Cao LR, Zhang C, Deng ZQ
… +5 more, Qiu YX, Zhang Z, Fan HY, Li J, Wu HB
Cell Prolif
· 2026 Mar · PMID 40754719
·
Full text
The maternal gene products stored in oocytes control the initial development of multicellular animals. Alteration within the dual allelic variants of transcription factor TCF12 causes female infertility; however, its imp...The maternal gene products stored in oocytes control the initial development of multicellular animals. Alteration within the dual allelic variants of transcription factor TCF12 causes female infertility; however, its impact on female reproduction is still unknown. In this study, we provide evidence that TCF12 is abundantly expressed within the nucleus of oocytes during growth at the germinal vesicle (GV) stage, recognising and binding to the functional domain of target genes to moderate transcriptional activity. The absence of Tcf12 in oocytes during the primordial follicular phase causes female sterility. Tcf12 does not participate in meiotic maturation; however, unlike Tcf3, it is essential for fertilisation and preimplantation development. Tcf12 maintains fertilisation competence by controlling the proper expression and location of cortical granules and protease ovastacin (encoded by Astl). In contrast, zygotes without TCF12 have a prolonged mitotic cell cycle upon a decrease in protein phosphatase 2A (PP2A) activity inhibition, resulting in zygotic genome activation (ZGA) failure during the 2-cell stage. Maternal knockout embryos gradually lose their developmental potential in subsequent developmental processes. These observations indicate that the maternal effect induced by Tcf12 ensures preimplantation development.
Yao C, Jin L, Zhong J
… +13 more, Huang Q, Bao Z, Zhou S, Wang C, Li H, Yuan X, Wang Z, Du N, Yu J, Chen H, Zhang X, Ge H, Wu J
Cell Prolif
· 2026 Feb · PMID 40749978
·
Full text
Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesi...Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.
Wang M, Cao Y, Ren C
… +9 more, Wang K, Wang Y, Wu X, Mao J, Liang Q, Zhang Q, Lu H, Xu X, Cong YS
Cell Prolif
· 2026 Feb · PMID 40745979
·
Full text
Melanoma is the most serious type of skin cancer. About half of all melanomas have activating BRAF mutations. Targeted therapy for malignant melanoma with BRAF inhibitor (BRAFi) or its combination with MEK inhibitor (MEK...Melanoma is the most serious type of skin cancer. About half of all melanomas have activating BRAF mutations. Targeted therapy for malignant melanoma with BRAF inhibitor (BRAFi) or its combination with MEK inhibitor (MEKi) improves the clinical outcomes of patients, but resistance develops invariably. The underlying mechanisms remain incompletely understood. Here, we show that caveolae number is increased in both BRAFi and BRAFi + MEKi-resistant melanoma cells, and the expression of the critical caveolae component PTRF is significantly upregulated in drug-resistant melanoma cell lines and tumour tissues. Knockdown of PTRF in drug-resistant cells reduces proliferation with increased apoptosis, whereas ectopic expression of PTRF confers resistance on parental cells to BRAFi or BRAFi + MEKi. On the contrary, the knockdown of PTRF in parental cells reduces their ability to acquire drug resistance induced by BRAFi treatment. Interestingly, we find that the expression of EGFR is increased along with PTRF and caveolin-1 in drug-resistant cells and in PTRF transduced parental cells, whereas knockdown of PTRF results in down-regulation of EGFR expression and attenuates drug resistance of parental cells induced by PTRF expression. Together, these results suggest that PTRF contributes to therapy resistance through upregulating EGFR in melanoma cells.
Xie D, Wang Y, Cheng W
… +6 more, Yan M, Li K, Wu X, Wu J, Zhang Z, Dai Y
Cell Prolif
· 2026 Mar · PMID 40741714
·
Full text
Cuproptosis, a copper-dependent cell death mechanism driven by tricarboxylic acid (TCA) cycle collapse, shows limited efficacy in hypoxic or glycolytic renal cell carcinoma (RCC). Here, through systematic screening of 68...Cuproptosis, a copper-dependent cell death mechanism driven by tricarboxylic acid (TCA) cycle collapse, shows limited efficacy in hypoxic or glycolytic renal cell carcinoma (RCC). Here, through systematic screening of 688 glycolysis inhibitors combined with elesclomol (ES), we identified PIK-III as a potent cuproptosis sensitiser. Multi-omics analysis revealed that PIK-III restores sensitivity by rewiring thiamine metabolism. Mechanistically, PIK-III induces macropinocytosis, enabling thiamine uptake to replenish thiamine pyrophosphate (TPP), which activates pyruvate dehydrogenase E1-alpha 1 (PDHA1) and redirects pyruvate into the TCA cycle. Concurrently, ES-induced DLAT oligomerisation disrupts TCA flux, creating a metabolic crisis. In vivo, PIK-III synergises with ES to suppress tumour growth in xenograft and patient-derived models without systemic toxicity. Our work uncovers a metabolic vulnerability in cuproptosis-resistant RCC and positions PIK-III as a therapeutic candidate to overcome resistance via dual targeting of thiamine transport and mitochondrial dysfunction.
Wang J, Yu M, Liu H
… +7 more, Sun K, Geng C, Liu H, Feng H, Liu Y, Zhao H, Han D
Cell Prolif
· 2026 Mar · PMID 40739677
·
Full text
Keratinocyte differentiation factor 1 (Kdf1) reportedly plays a significant role in enamel formation. In terms of tooth morphogenesis, human KDF1 variants are associated with crown morphological abnormalities, suggesting...Keratinocyte differentiation factor 1 (Kdf1) reportedly plays a significant role in enamel formation. In terms of tooth morphogenesis, human KDF1 variants are associated with crown morphological abnormalities, suggesting that Kdf1 may also be essential for tooth morphogenesis. However, the involvement of Kdf1 in tooth morphogenesis and its underlying mechanisms remains unclear. In this study, we observed that mice lacking epithelial Kdf1 (K14-Cre;Kdf1 ) displayed rounded and blunt molar cusps, resembling the morphological anomalies observed in patients with Kdf1 variants. 5-Ethynyl-2'-deoxyuridine assays revealed increased proliferative activity of the inner enamel epithelial (IEE) cells in the cusp region of K14-Cre;Kdf1 mice during the bell stage. RNA sequencing and western blot analysis confirmed the overactivation of PI3K/AKT/mTOR signalling in the molar IEE cells of K14-Cre;Kdf1 mice. Furthermore, in utero microcapillary injection of the PI3K/AKT/mTOR pathway inhibitor LY294002 partially rescued the molar cusp defects in K14-Cre;Kdf1 mice. Collectively, our findings provide in vivo evidence supporting the regulatory role of Kdf1 in molar cusp morphogenesis, highlighting its function in modulating dental epithelial cell proliferation via the PI3K/AKT/mTOR signalling pathway.
Yang Y, Sun R, Lan Z
… +14 more, Ma Q, Wu G, Xue D, Chen Z, Su Y, Ma Y, Chen X, Yan J, Ma L, He X, Tian K, Ma X, Lin X, Jin Q
Cell Prolif
· 2026 Mar · PMID 40730513
·
Full text
Transcriptomics studies have identified integrin receptor β2 subunit (ITGB2) as a core gene in osteoarthritis (OA), strongly linked to osteoclast function in the subchondral bone. However, the mechanism through which ITG...Transcriptomics studies have identified integrin receptor β2 subunit (ITGB2) as a core gene in osteoarthritis (OA), strongly linked to osteoclast function in the subchondral bone. However, the mechanism through which ITGB2 regulates osteoclast function in OA remains unclear. In this study, we found that ITGB2 was negatively correlated with ITGB1 in the human subchondral bone. Proteomic analysis indicated that integrin binding is crucial in OA subchondral bone, with ITGB2 identified as a significantly upregulated protein in OA. In vitro experiments using immunoprecipitation and bimolecular fluorescence complementation revealed that ITGB2, but not ITGB1, directly interacts with Rac1 during osteoclast differentiation. Activated Rac1 promotes osteoclast differentiation and bone resorption through several mechanisms. ITGB2 knockdown reduced Rac1-GTP levels and increased ITGB1 expression. ITGB2 inhibition reduced actin ring formation and microtubule migration to the cell edge during osteoclast differentiation. Additionally, overexpression of ITGB1 in ITGB2-knockdown cells not only further suppressed ITGB2 expression but also exacerbated the inhibition of osteoclast differentiation. In a DMM mouse model, ITGB2 was associated with osteoclast activity in the subchondral bone. ITGB2 knockdown significantly reduced bone resorption and slowed OA progression by inhibiting osteoclastogenesis. In conclusion, our study identified a novel mechanism for the reciprocal regulation of integrin subunits. Moreover, inhibition of the ITGB2 signalling pathway slows subchondral bone remodelling in osteoarthritis by inhibiting osteoclast differentiation, offering a potential strategy for targeted therapeutic interventions.
Liang W, Li G, Wang Y
… +11 more, Wei W, Chen R, Sun S, Gan D, Yi H, Schaefke B, Hu Y, Zhou Q, Li W, Cui H, Chen W
Cell Prolif
· 2026 Mar · PMID 40729530
·
Full text
Differences in gene expression, which arise from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity durin...Differences in gene expression, which arise from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity during evolution. On one hand, changes in the cis-elements located in the vicinity of target genes affect TF binding and/or local chromatin environment, thereby modulating gene expression in cis. On the other hand, alterations in trans-factors influence the expression of their target genes in a more pleiotropic fashion. Although the evolution of amino acid sequences is much slower than that of non-coding regulatory elements, particularly for the TF DNA binding domains (DBDs), it is still possible that changes in TF-DBD might have the potential to drive large phenotypic changes if the resulting effects have a net positive effect on the organism's fitness. If so, species-specific changes in TF-DBD might be positively selected. So far, however, this possibility has been largely unexplored. By protein sequence analysis, we observed high sequence conservation in the DBD of the TF caudal-type homeobox 2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent. There were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Moreover, Cdx2 binding is largely divergent between mouse and rat; the transcriptional effect induced by Cdx2 is conserved to a much larger extent.
Xiao J, Hu H, Zou M
… +4 more, Li C, Deng D, Chen X, Liu J
Cell Prolif
· 2025 Oct · PMID 40706634
·
Full text
MFG-E8 promotes oxidative stress by upregulating NOX4 and activating the MAPK pathway, which increases ROS production and affects vascular smooth muscle cell (VSMC) apoptosis, thereby driving the progression of abdominal...MFG-E8 promotes oxidative stress by upregulating NOX4 and activating the MAPK pathway, which increases ROS production and affects vascular smooth muscle cell (VSMC) apoptosis, thereby driving the progression of abdominal aortic aneurysm (AAA). Resveratrol can inhibit the expression and function of MFG-E8, reduce ROS generation, and lower the incidence and severity of AAA, making it a potential therapeutic agent for AAA.
Sriwattanapong K, Thaweesapphithak S, Khamwachirapitak C
… +7 more, Sae-Ear P, Prommanee S, Sa-Ard-Iam N, Phothichailert S, Jung HS, Shotelersuk V, Porntaveetus T
Cell Prolif
· 2026 Feb · PMID 40693438
·
Full text
Amelogenesis imperfecta type 1G (AI1G), also known as Enamel-Renal-Gingival Syndrome (ERGS), is an autosomal recessive disorder caused by variants in FAM20A, encoding a Golgi apparatus protein crucial for protein process...Amelogenesis imperfecta type 1G (AI1G), also known as Enamel-Renal-Gingival Syndrome (ERGS), is an autosomal recessive disorder caused by variants in FAM20A, encoding a Golgi apparatus protein crucial for protein processing and secretion. AI1G presents with enamel defects, nephrocalcinosis and gingival overgrowth. Building upon our previous findings demonstrating the impact of FAM20A insufficiency on deciduous dental pulp cells, this study investigated the molecular mechanisms underlying gingival fibromatosis in AI1G. RNA sequencing of gingival fibroblasts from an AI1G patient revealed widespread differential gene expression (DEG). Gene Ontology (GO) analysis demonstrated enrichment of DEGs in biological processes related to cell adhesion, differentiation, proliferation (including positive regulation and cell division), cell cycle regulation, apoptosis and signal transduction. Pathway analysis (Reactome and KEGG) further highlighted the dysregulation of signalling pathways, including Wnt, TGF-β, cell cycle, DNA replication, Rho GTPase signalling and extracellular matrix organisation. Functional assays confirmed these findings, revealing delayed initial attachment and spreading, impaired osteogenic differentiation (evidenced by reduced mineralization and downregulation of DLX5, OCN, RUNX2 and OPN), enhanced cell cycle progression and proliferation (increased colony size and proliferation rates, along with a shift from G0/G1 to G2/M phase) and suppressed apoptosis in FAM20A-insufficient fibroblasts. These results suggest that FAM20A plays a critical role in regulating fundamental processes in gingival fibroblasts, and its insufficiency contributes to the gingival fibromatosis phenotype observed in AI1G through the disruption of cell adhesion, differentiation, proliferation and apoptosis. This study proposes novel insights into the pathogenesis of AI1G and highlights potential therapeutic targets for this complex disorder.
Far BF, Akbari M, Habibi MA
… +2 more, Katavand M, Nasseri S
Cell Prolif
· 2025 Nov · PMID 40685330
·
Full text
CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores re...CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.
Yi X, Deng X, Deng J
… +12 more, Li C, Peng H, Du Y, Li Q, Yan X, Hu X, Zheng Y, Chen S, Xiong T, Xu D, Chen L, Hao L
Cell Prolif
· 2026 Apr · PMID 40670295
·
Full text
Osteosarcoma (OS) is a primary bone tumour that occurs mostly in adolescents and is associated with a high degree of malignancy, early metastasis, and poor prognosis. Pyropheophorbide-a methyl ester-Photodynamic therapy...Osteosarcoma (OS) is a primary bone tumour that occurs mostly in adolescents and is associated with a high degree of malignancy, early metastasis, and poor prognosis. Pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT) is a new approach for the clinical treatment of osteosarcoma that develops after surgery and radiotherapy; however, the presence of MPPa-PDT resistance in osteosarcoma greatly limits its efficacy. In this study, we found that Rho-associated coiled-coil containing protein kinase 2 (ROCK2) expression increased in osteosarcoma cells after MPPa-PDT treatment. ROCK2 inhibition results in osteosarcoma sensitivity to MPPa-PDT and is accompanied by a decrease in cellular autophagy levels. Rescue experiments further showed that ROCK2 mediates MPPa-PDT resistance in osteosarcoma by regulating autophagy. Mechanistic studies have shown that ROCK2 mediates autophagy in osteosarcoma cells by regulating the Hippo signalling pathway. ROCK2 overexpression resulted in increased levels of the ROCK2-Salvador homology 1 (SAV1) complex and decreased levels of the mammalian STE20-like protein kinase 1 (MST1)-SAV1 complex, thereby inhibiting activation of the Hippo pathway, which in turn led to osteosarcoma MPPa-PDT resistance by regulating cellular autophagy. ROCK2 competes with MST1 for binding to the aa 28-198 region of SAV1. We also confirmed from a clinical perspective that ROCK2 is an independent prognostic factor in patients with osteosarcoma, is associated with worse patient prognosis, and correlates with the Hippo pathway. Targeted inhibition of ROCK2 by screening for J059-0149 increases the sensitivity of osteosarcoma to MPPa-PDT. In conclusion, our study establishes a novel mechanism to reverse MPPa-PDT resistance in osteosarcoma by targeting ROCK2-mediated autophagy, providing new targets and research ideas for the clinical treatment of osteosarcoma MPPa-PDT resistance.