Cellular & Molecular Biology Letters最新文献

{"title":"Cannabidiol alleviates traumatic brain injury-induced neuronal damage and cognitive deficits by inhibiting ferroptosis via the TRPV1/MCU/PI3K/Akt pathway.","authors":"Yejia Xu, Xiong Li, Zhiya Gu, Xuehua Chen, Yang Zhao, Bowen Jia, Yumeng Wu, Rui Wan, Qianqian Li, Tao Wang, Chengliang Luo","doi":"10.1186/s11658-026-00983-z","DOIUrl":"10.1186/s11658-026-00983-z","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is a common surgical traumatic condition that poses a significant threat to human health and working capacity. However, effective treatments to improve its prognosis remain limited. Cannabidiol (CBD), a naturally occurring compound extracted from the cannabis plant, exhibits multiple pharmacological effects through diverse molecular targets. To date, the role and underlying molecular mechanisms of CBD in the context of TBI have not been fully elucidated. In this study, we investigated the specific effects of CBD following TBI and explored its underlying mechanisms.</p><p><strong>Methods: </strong>An in vitro ferroptosis model was established using HT-22 cells, and an in vivo TBI model was established in mice. Techniques such as Western blotting, immunofluorescence staining, and behavioral analysis were employed to evaluate the effects of CBD on ferroptosis, pathological changes, and neurological function after TBI, as well as to explore the associated molecular mechanisms.</p><p><strong>Results: </strong>CBD significantly alleviated ferroptosis, neuronal injury, and cognitive dysfunction following TBI in vitro and in vivo. Further investigation revealed that CBD mitigated mitochondrial dysfunction by reducing Ca^2⁺ overload via the TRPV1/MCU signaling pathway. Moreover, utilizing methodologies such as recombinant adeno-associated virus (rAAV) injection and transcriptome analysis, mitochondrial calcium uniporter (MCU) was identified as a core regulator of ferroptosis in neurons following TBI. Neuronal MCU knockdown attenuated the progression of ferroptosis and improved neurological outcomes after TBI. Finally, integrated findings confirmed that CBD inhibit ferroptosis after TBI through the TRPV1/MCU/PI3K/Akt signaling pathway.</p><p><strong>Conclusions: </strong>CBD inhibits ferroptosis, at least in part, via the TRPV1/MCU/PI3K/Akt signaling pathway, thereby alleviating TBI-induced neuronal damage and cognitive deficits. In addition, these findings indicate that CBD exhibits a potent anti-ferroptotic effect and may serve as a promising therapeutic agent for TBI.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitigating nucleus pulposus cell senescence in intervertebral disk degeneration: the role of nodakenin in SIRT6 and PINK1/Parkin-associated mitophagy signaling.","authors":"Daqian Zhou, Liquan Wang, Yang Zhou, Jiale Lv, Chao Song, Yongliang Mei, Tao Liu, Taotao Wu, Fei Yu, Zongchao Liu","doi":"10.1186/s11658-026-00968-y","DOIUrl":"10.1186/s11658-026-00968-y","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on H₂O₂-induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"piR-26681 suppresses ovarian cancer progression by enhancing METTL3/METTL14-mediated m⁶A modification of FBXO16 and impairing DNA repair via MORF4L1 degradation.","authors":"Jie-Lin Wang, Qing-Hua Wu, Jing Yuan, Hai-Juan Bao, Xiang-Chun Huang, Jia-Chen Cheng, Yang Zhao, Shuo Chen","doi":"10.1186/s11658-026-00969-x","DOIUrl":"10.1186/s11658-026-00969-x","url":null,"abstract":"<p><strong>Background: </strong>Survival rates for ovarian cancer drop sharply at late-stages due to late diagnosis. Although PARP inhibitors are effective in homologous recombination-deficient (HRD) tumors, their efficacy in homologous recombination (HR)-proficient ovarian cancer remains limited, highlighting the need for novel molecular targets to inhibit tumor progression and improve patient outcomes.</p><p><strong>Methods: </strong>Differentially expressed piRNAs were screened using ovarian cancer tissues from early- and advanced-stage patients. Functional studies were performed in ovarian cancer cell lines, xenograft models, and patient-derived organoids. Molecular mechanisms were investigated using RNA pulldown, RNA immunoprecipitation, MeRIP-seq, ubiquitination assays, and DNA damage analyses.</p><p><strong>Results: </strong>We identified piR-26681 as a piRNA significantly downregulated in advanced-stage ovarian cancer and associated with favorable prognosis. Functional assays demonstrated that piR-26681 suppressed ovarian cancer progression in cell lines, xenograft mouse models, and patient-derived organoids. Mechanistically, piR-26681 directly interacted with METTL3 and METTL14, enhancing their interaction, reducing their ubiquitination, and thereby increasing their protein stability. This stabilization promoted global m⁶A methylation in ovarian cancer cells. Increased m⁶A modification subsequently enhanced the stability of FBXO16 mRNA through the m⁶A reader IGF2BP2, leading to elevated FBXO16 expression. As an E3 ubiquitin ligase, FBXO16 further mediated the ubiquitination and degradation of MORF4L1, a key regulator of homologous recombination repair. Loss of MORF4L1 impaired HR repair, increased DNA damage accumulation, and sensitized ovarian cancer cells to the PARP inhibitor niraparib.</p><p><strong>Conclusions: </strong>Our study identifies a novel piR-26681-METTL3/METTL14-FBXO16-MORF4L1 regulatory axis that impairs DNA repair and suppresses ovarian cancer progression. piR-26681 represents a promising therapeutic target for sensitizing HR-proficient ovarian cancers to DNA-damaging therapies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human primordial germ cell heterogeneity in vitro is associated with distinctive biological states.","authors":"Young Sun Hwang, Qiu Ya Wu, Sissy E Wamaitha, Amander T Clark","doi":"10.1186/s11658-026-00986-w","DOIUrl":"10.1186/s11658-026-00986-w","url":null,"abstract":"<p><strong>Background: </strong>Primordial germ cells (PGCs) exhibit molecular heterogeneity during development, yet whether this reflects functionally distinct states remains unclear.</p><p><strong>Methods: </strong>We investigated the functional significance of DND1 translation heterogeneity in human PGC-like cell (hPGCLC) extended culture, using dual fluorescent reporters, transcriptomic analysis and functional assays.</p><p><strong>Results: </strong>Single-cell RNA-sequencing revealed that DND1 + hPGCLCs are enriched in RNA regulatory genes including those associated with P-bodies and translational control. DND1 + cells exhibit reduced proliferation, cell cycle exit, and elevated nuclear expression P27 (CDKN1B). These cells also maintained stable expression of genes essential for germ cell differentiation. Notably, BMP2 supplementation stabilized DND1 translation without altering mRNA levels or proliferation rates.</p><p><strong>Conclusions: </strong>Together, these findings demonstrate that post-transcriptional regulation by DND1 coordinates cell cycle dynamics with distinct cellular state in human germ cells, highlighting critical translational control mechanisms in germline development.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of FSP1-regulated ferroptosis and therapeutic implications in various cancers.","authors":"Congyue Zhang, Chao Sun, Yuemin Nan","doi":"10.1186/s11658-026-00978-w","DOIUrl":"10.1186/s11658-026-00978-w","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In addition to the canonical glutathione peroxidase 4 pathway, ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2, functions as a major glutathione-independent suppressor of ferroptosis. Current evidence indicates that FSP1 restrains lipid peroxidation mainly through the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent coenzyme Q10 axis. FSP1 has also been implicated in the noncanonical vitamin K cycle, which further expands its redox role. Emerging studies suggest that liquid-liquid phase separation and membrane repair may broaden the functional landscape of FSP1, although these mechanisms remain less fully defined. We then summarize the multilayer regulation of FSP1 and discuss how it contributes to ferroptosis resistance, tumor adaptation, and therapeutic responses in cancer. Finally, we review current preclinical efforts to target FSP1, with emphasis on small-molecule inhibitors, mechanism-based combinations, candidate biomarkers, and major translational challenges. Together, these observations position FSP1 as an important determinant of ferroptosis resistance in cancer and a promising focus for further mechanistic and translational study.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL17 signaling promotes oocyte developmental competence acquisition during maturation.","authors":"Huaxing Zhao, Xiaohua He, Junsong Shi, Xiao Wu, Yalin Liang, Xingwang Wang, Zheng Ao, Xianjun Zhang, Yuxing Zhang, Yanan Li, Yiqian Zhang, Yazheng Dong, Jingfeng Peng, Yunfei Hou, Rong Zhou, Fang Zeng, Linjun Hong, Ting Gu, Huaqiang Yang, Jie Yang, Zheng Xu, Sixiu Huang, Gengyuan Cai, Zicong Li, Zhenfang Wu","doi":"10.1186/s11658-026-00971-3","DOIUrl":"10.1186/s11658-026-00971-3","url":null,"abstract":"<p><strong>Background: </strong>Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturation is essential for reproductive biology and medicine. Follicular fluid (FF) is an important microenvironment governing oocyte maturation.</p><p><strong>Methods: </strong>A tandem mass tags (TMT)-based comparative FF proteomic analysis was employed to identify FF proteins that are potentially crucial for oocyte maturation. A very large number of pig and mouse oocytes (approximately 20,000) and embryos (over 13,000, including somatic cell nuclear transfer, parthenogenetic activation, and in vitro fertilization embryos) were used to investigate the effects of identified FF proteins on in vitro oocyte maturation and subsequent in vitro and in vivo embryo development. RNA sequencing, quantitative PCR, enzyme-linked immunosorbent assays, and immunofluorescence were used to study the expression patterns and action mechanisms of identified FF proteins in oocytes. In addition, intra-oocyte levels of glutathione and reactive oxygen species were measured to assess redox homeostasis.</p><p><strong>Results: </strong>Interleukin 17D (IL17D) was identified as an important FF protein and it is significantly upregulated in porcine FF during oocyte maturation. IL17D promotes oocyte maturation by enhancing bidirectional communication between oocytes and cumulus cells, via upregulating CX43 expression and transzonal projections, which helps to maintain oocyte redox homeostasis and nuclear-cytoplasmic synchrony. IL17D treatment of oocytes enhances subsequent in vitro and in vivo full-term embryo development by modulating lipid metabolism and histone modification reprogramming. IL17D exerts its function via activating IL17 signaling through binding to CD93. Two other IL17 family members, IL17A and IL17F, also enhance oocyte maturation quality. IL17D displays a conserved expression pattern and function in pig and mouse oocytes.</p><p><strong>Conclusions: </strong>This study reveals the critical roles of IL17D in regulating oocyte developmental competence acquisition during maturation by activating IL17 signaling. The findings provide valuable insights into the molecular mechanisms underlining oocyte developmental potential acquisition and may help to develop methods for efficient production of oocytes for assisted reproduction.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM-1-dependent macrophage infiltration mediates visceral hypersensitivity via vlPAG GABAergic neuron activation in a mouse model of inflammatory bowel disease.","authors":"Zi-Ming Zhou, Wei Song, Miao-Miao Guo, Yuan-Qing Chu, Lu-Bin Wang, Peng Cheng, Jing-Wen Huang, Ting Su, Xu-Feng Huang, Yong-Mei Zhang","doi":"10.1186/s11658-026-00980-2","DOIUrl":"10.1186/s11658-026-00980-2","url":null,"abstract":"<p><strong>Background: </strong>Visceral pain is a common symptom of inflammatory bowel disease (IBD). Although triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to induce infiltration of peripheral immune cells into the central nervous system, the specific contribution of peripheral monocytes/macrophages (Mo/MΦ) to visceral pain in IBD remains elusive. This study aimed to investigate the effect of TREM-1-dependent macrophage infiltration in the periaqueductal gray (PAG) on visceral pain and the underlying mechanisms in IBD.</p><p><strong>Methods: </strong>Male C57BL/6 J or Trem1^-/- mice were fed 2% dextran sodium sulfate (DSS) for 7 days to induce colitis. Flow sorting, flow cytometry, and western blot were employed to isolate, transfer, and detect immune cells as well as TREM-1 expression. Immunofluorescence and in vitro brain slice electrophysiology were used to assess the activity of GABAergic neurons. Visceral pain was evaluated using the abdominal withdrawal reflex (AWR) score, visceral pain threshold, and electromyography (EMG).</p><p><strong>Results: </strong>Peripheral Mo/MΦ infiltration into the PAG played a dominant role in enhancing ventrolateral PAG (vlPAG) GABAergic neuronal activity in mice with acute colitis, compared with the relatively minor contributions of resident microglia and peripheral neutrophils. This promoted acute visceral pain during intestinal inflammation with visceral pain persisting into the remission phase. To validate the role of peripheral TREM-1-expressing Mo/MΦ in visceral pain, microinjection of Ly6C⁺ monocytes into the vlPAG led to activation of vlPAG GABAergic neurons and an increase in visceral pain sensitivity. Pharmacological inhibition and gene knockout of TREM-1 both reduced Mo/MΦ infiltration, leading to decreased vlPAG GABAergic neuronal activity and mitigatory visceral pain.</p><p><strong>Conclusions: </strong>Our study identifies peripheral Mo/MΦ TREM-1 as a mediator promoting visceral pain via vlPAG GABAergic neuron activation. This finding presents a promising therapeutic approach for treating acute intestinal inflammation and visceral pain in colitis, while also offering a potential target for managing chronic visceral pain that persists in patients with IBD.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRKN mediates the ubiquitination of SCAF8 to reduce the mRNA stability of KLF5 and its transcriptional activation of EFNA3 in colorectal cancer.","authors":"Ye Song, Yangsheng Yu, Bo Zhang, Xiao Zhang","doi":"10.1186/s11658-026-00974-0","DOIUrl":"10.1186/s11658-026-00974-0","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation in glycolysis within the tumor microenvironment is a hallmark in the context of colorectal cancer (CRC). We aimed to identify critical drivers of glycolysis in CRC and decipher the underlying mechanism.</p><p><strong>Methods: </strong>Through combined gene interference in CRC cells using lentivirus and treatment with glycolysis activator DASA-58, we measured glycolytic flux to evaluate how molecular mechanisms influence tumor cell activity via glycolysis. CRC cells were cocultured with NK and CD8⁺ T cells to analyze the anti-tumor immune response. A patient-derived xenograft mouse model and a CMT93 cell-derived allograft mouse model were developed for analyzing CRC growth, metastasis, and immune evasion.</p><p><strong>Results: </strong>EFNA3 was elevated in CRC tissues and cell lines. The glycolytic activity, proliferative, migratory, invasive, and pro-angiogenic effects of the CRC cells were reduced, and the anti-tumor response of the CD⁸⁺ T and NK cells was enhanced after EFNA3 knockdown in CRC cells. Tumors formed by CMT93 cells with EFNA3 knockdown exhibited reduced metastasis and an increased proportion of anti-tumor immune cells infiltrated. Overexpression of KLF5 promoted EFNA3 transcription, and SCAF8 enhanced KLF5 mRNA stability. Downregulation of PRKN in CRC enhanced the SCAF8 protein expression through ubiquitination. PRKN upregulation blocked glycolysis and suppressed the malignant behavior of CRC cells, whereas the anticancer ability of PRKN was reversed by SCAF8/KLF5/EFNA3 overexpression.</p><p><strong>Conclusions: </strong>Activating the E3 ubiquitin ligase activity of PRKN to suppress EFNA3 expression represents a promising therapeutic strategy for the clinical treatment of CRC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NAT10/c-Myc positive feedback loop orchestrates tRNA ac⁴C modification and OTUB1-mediated protein stabilization to drive anaplastic thyroid carcinoma progression.","authors":"Bo Wei, Haixi Zhao, Shi Chang, Wenlong Wang","doi":"10.1186/s11658-026-00977-x","DOIUrl":"10.1186/s11658-026-00977-x","url":null,"abstract":"<p><strong>Background: </strong>Epitranscriptomic regulation of tRNA modifications has emerged as an important mechanism in cancer progression by influencing oncogenic translation. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with limited therapeutic options. Although N-acetyltransferase 10 (NAT10) is frequently overexpressed in multiple cancers, its functional role and therapeutic potential in ATC remain unclear.</p><p><strong>Methods: </strong>We employed integrated approaches including bioinformatics analyses,in vitro and in vivo assays, multi-omics profiling (mRNA-seq, Ribo-seq, tRNA RedaC-seq), and mechanistic studies (ChIP, LC-MS and ubiquitination assays) in ATC cell lines and xenograft models.</p><p><strong>Results: </strong>NAT10 is significantly upregulated in ATC and correlates with poor prognosis. Functional assay demonstrates that NAT10 enhances ATC cell proliferation and invasion in vitro and in vivo. The targeted inhibition of NAT10 using the small molecule inhibitor remodelin effectively suppresses ATC cell growth. Mechanistically, NAT10 forms a positive feedback loop with the transcription factor c-Myc: c-Myc transcriptionally activates NAT10, whereas NAT10 is associated with enhanced translation of c-Myc in conjunction with tRNA ac⁴C modification. NAT10 depletion reduces global translation efficiency, accompanied by decreased tRNA ac⁴C levels, and also affects c-Myc protein stability via the deubiquitinase OTUB1. Moreover, combined treatment with remodelin and doxorubicin exhibits synergistic antitumor effects in both in vitro and in vivo models.</p><p><strong>Conclusions: </strong>These findings identify a NAT10/c-Myc positive feedback loop associated with tRNA ac⁴C modification and protein stabilization in ATC. Targeting this regulatory axis with remodelin in combination with doxorubicin may represent a promising therapeutic strategy.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biased signaling of β2-adrenergic receptor in physiological and pathological states.","authors":"Yaxin Xu, Vincent Kawuribi, Joseph Adu-Amankwaah, Zheng Gong, Xinrui Li, Yixuan Lei, Zhenyu Wang, Parfait Botolo Sakava, Fengjie Zhao, Xiuhua Pan, Cui Li, Hong Sun, Lu Fu","doi":"10.1186/s11658-026-00976-y","DOIUrl":"10.1186/s11658-026-00976-y","url":null,"abstract":"<p><p>The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes. Unlike the classical β1AR, the β2AR exhibits unique biased signaling properties. Selective activation of specific downstream pathways, such as the β-arrestin pathway, ERK1/2, and PI3K/Akt, is mediated by ligand binding via biased signaling by a specific G protein, resulting in distinct cellular responses. This review provides an in-depth analysis of the complex mechanisms governing biased β2AR-mediated signaling, highlighting its crucial roles in cardiovascular health, respiratory pathologies, neuroregulatory mechanisms, immunological regulation, and tumor biology. Although β2AR-biased signaling is a well-established phenomenon, its underlying mechanisms and pathophysiological implications remain incompletely elucidated compared with traditional signaling modes. This paper summarizes recent studies on the specificity of β2AR signaling and examines its potential therapeutic applications. Future research should concentrate on clarifying the structural foundations of biased signaling, developing biased ligands, and using these discoveries for precision therapeutics. The therapeutic potential of β2AR-biased signaling is being fully explored, which may open new avenues for personalized treatment of various diseases and bring breakthroughs to the field of clinical medicine.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}