Cellular & Molecular Biology Letters最新文献

{"title":"Lactobacillus acidophilus abolishes oxalate-mediated renal epithelial barrier disruption and calcium oxalate monohydrate crystal adhesion to renal epithelial cells.","authors":"Anantaya Putpim, Chadanat Noonin, Paranyu Chawanpaiboon, Onnipa Pawano, Somsakul Phuangkham, Paleerath Peerapen, Visith Thongboonkerd","doi":"10.1186/s11658-026-00985-x","DOIUrl":"https://doi.org/10.1186/s11658-026-00985-x","url":null,"abstract":"<p><strong>Background: </strong>It is generally known that kidney stone disease (KSD) is associated with alterations in urinary microbiome, but the roles of the urinary microbiome in KSD pathogenesis remain unclear.</p><p><strong>Methods: </strong>This study addressed the impact of Lactobacillus acidophilus (a commensal bacterium found in normal urine) on renal epithelial integrity, calcium oxalate monohydrate (COM) crystal-cell adhesion, expression of membrane receptors of COM crystals, and oxalate degradation under oxalate-induced stress (a known inducer of KSD). Inner medullary collecting duct cells (mIMCD-3) were cultured for 24 h under control or oxalate-induced (by 0.6 mM sodium oxalate; NaOx) conditions without or with L. acidophilus (at 1 × 10³ colony-forming unit (CFU)/ml) co-incubation.</p><p><strong>Results: </strong>NaOx reduced transepithelial resistance (TER) of the mIMCD-3 monolayer and downregulated ZO-1, a tight junction (TJ) protein. Additionally, NaOx enhanced the COM crystal-binding capability of mIMCD-3 cells by upregulating a COM crystal receptor, annexin A2, on cell membranes. Such harmful effects of NaOx were abolished when mIMCD-3 cells were co-cultured with L. acidophilus. Moreover, culturing L. acidophilus in artificial urine (AU) supplemented with NaOx for 24 h revealed that the oxalate level in AU decreased, suggesting the oxalate-degrading activity of the bacterium in an AU environment.</p><p><strong>Conclusions: </strong>L. acidophilus prevented oxalate-mediated renal epithelial barrier disruption and COM crystal adhesion to renal epithelial cells by preserving ZO-1 and annexin A2 expression at their basal levels, at least in part, via its oxalate-degrading property.</p><p><strong>Clinical trial number: </strong>Not applicable (This is not a clinical trial).</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenin alleviates lipotoxicity-induced impairment of skin wound healing.","authors":"Min Fu, Yi Wang, Chunyi Wu, Xiaoyu Deng, Zaiyong Zheng, Yang Yu, Yajun Yu, Lunkun Ma, Jianguo Feng, Chunxiang Zhang","doi":"10.1186/s11658-026-00970-4","DOIUrl":"https://doi.org/10.1186/s11658-026-00970-4","url":null,"abstract":"<p><p>Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic stress has been unknown. Here, we demonstrate for the first time that Angiogenin effectively protects against lipotoxicity-induced delayed skin repair. In a cellular lipotoxicity model induced by oleic and palmitic acids (OPA) using human umbilical vein endothelial cells (HUVECs), the levels of Angiogenin decreased in a time- and dose-dependent manner. Meanwhile, a similar reduction was also observed in the skin tissue of high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE)^-/- mice. Restoring Angiogenin levels significantly enhanced endothelial proliferation, migration, and angiogenesis, rescuing OPA-induced impairment. Through RNA-seq and subsequent validations, we provide novel mechanistic insight into Angiogenin's protective action: Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. Critically, we show that the Angiogenin-mediated endothelial rescue is strictly dependent on this Cav1 upregulation. Furthermore, topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE^-/- and high-fat diet/STZ-induced diabetic mice. Collectively, our study unveils a novel Angiogenin-Cav1 axis in endothelial protection, positioning Angiogenin as a promising therapeutic candidate for lipotoxicity-induced impairment of skin wound healing.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SLK protects against cerebral ischemia-reperfusion injury by regulating USP8-mediated HIF-1α stabilization and RhoA/ROCK activation.","authors":"Yuetao Wen, Zhiyu Xiong, Zhiyuan Wang, Ya He, You Wang, Yuan Tao, Liping Huang, Chen Gong, Shuyu Jiang, Guo Du, Yangmei Chen, Tao Xu","doi":"10.1186/s11658-026-00988-8","DOIUrl":"https://doi.org/10.1186/s11658-026-00988-8","url":null,"abstract":"<p><strong>Introduction: </strong>Acute ischemic stroke (AIS) represents a major global contributor to mortality and chronic disability, with few effective therapeutic targets available. Identifying druggable genes associated with AIS is therefore critical for developing novel interventions.</p><p><strong>Methods: </strong>A comprehensive approach combining Mendelian randomization, multi-omics integration, and machine learning was employed to identify candidate druggable genes. Causal relationships were confirmed through genetic colocalization, and candidate genes were further validated in a retrospective clinical cohort comprising 60 patients who experienced AIS and 30 healthy controls. Functional and mechanistic investigations were performed using a male mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, oxygen-glucose deprivation/reperfusion (OGD/R) in HT22 cells, and 293 T cells.</p><p><strong>Results: </strong>SLK emerged as a genetically causal AIS gene and a central component of the optimal predictive model. Plasma SLK levels were elevated in patients who experienced AIS, demonstrating strong diagnostic and prognostic value and serving as an independent predictor of unfavorable 3-month outcomes after adjusting for age, sex, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Knockdown of SLK conferred neuroprotection both in vivo and in vitro. SLK interacted with and phosphorylated the deubiquitinase USP8, increasing its activity and suppressing K48-linked polyubiquitination and degradation of HIF-1α. HIF-1α was stabilized following activation of the RhoA/ROCK signaling pathway, aggravating ischemic injury, whereas USP8 overexpression mitigated the neuroprotective effects of SLK knockdown.</p><p><strong>Conclusions: </strong>These findings identify SLK as a neuron-specific proischemic factor and a potential therapeutic target, elucidate the SLK-USP8-HIF-1α-RhoA/ROCK pathway as a key mechanistic pathway, and highlight plasma SLK as a promising diagnostic and prognostic biomarker with translational relevance.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Targeting fibroblast activation protein-α to treat renal fibrosis.","authors":"Li Gong, Xinyu Lu, Na Ma, Tao Lu, Yuhong Gong, Liwei Hao, Weikang Xu, Qianbing Zhang, Xiaolan Chen, Qinglin Mo, Jiexing Tan, Henrique de Paula Lemos, Alexander Speechley, Wenwei Tu, Jianpiao Cai, Lei Huang, Wei Zhu, Sha Wu","doi":"10.1186/s11658-026-00967-z","DOIUrl":"10.1186/s11658-026-00967-z","url":null,"abstract":"","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":"31 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13317259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359537","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":"Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy.","authors":"Wenlong Zhu, Yanjie Zhang, Runze Jiang, Li Wang, Jin Ding","doi":"10.1186/s11658-026-00979-9","DOIUrl":"https://doi.org/10.1186/s11658-026-00979-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics of its tissue structure, HCC has a high propensity for metastasis. Unfortunately, most patients are diagnosed at the middle or advanced stage and present with metastasis. The occurrence of metastasis often indicates a severe deterioration of the condition and the loss of an opportunity for radical treatment. Thus, immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the first-line treatment for patients with advanced metastasis. The tumor immune microenvironment (TIME), as the core immune component within tumors, has been confirmed to be significantly associated with metastasis through the complex crosstalk with suppressive immune cells. This crosstalk dynamically participates in the metastatic cascade of HCC, assisting tumors in completing invasion and diffusion. The goal of immunotherapy is to restore the function of exhausted immune cells in the TIME. However, the complex immunosuppressive microenvironment often weakens treatment responses, posing severe challenges to the application of immunotherapies. Accordingly, there is an urgent need to deeply investigate the crosstalk among diverse cell types within the immunosuppressive microenvironment and to systematically elucidate the impact of such intercellular crosstalk on the HCC metastasis as well as the response to immunotherapy, so as to improve the clinical benefit rate of immunotherapy for patients with metastatic HCC. This review focuses on the dual role of immune cells in HCC metastasis and the novel mechanisms by which they promote the HCC metastatic cascade. It systematically summarizes current therapeutic strategies targeting the immunosuppressive microenvironment to combat HCC metastasis. On this basis, it prospectively proposes the future development direction of immunotherapy, providing more effective guidance for the clinical diagnosis and treatment of patients with metastatic HCC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.","authors":"Renjie Xie, Ruixue Geng, Yuchen Wang, Chenyue Zhan, Xinyue Deng, Yanting Duan, Juyong Liang, Jiafeng Wang, Ruimin Liang, Jingyan Ge, Minghua Ge, Xiaozheng Zhu","doi":"10.1186/s11658-026-00973-1","DOIUrl":"10.1186/s11658-026-00973-1","url":null,"abstract":"<p><strong>Background: </strong>Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes.</p><p><strong>Methods: </strong>In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8⁺ T-cell infiltration and cytokine secretion.</p><p><strong>Results: </strong>This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8⁺ T-cell infiltration.</p><p><strong>Conclusions: </strong>This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.</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/PMC13459170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337848","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":"Sperm surface protein disulfide isomerase ERp57 is crucial for mammalian fertilization but functions independently of IZUMO1.","authors":"Emily Forster, Sophie Dupuis, Côme Ialy-Radio, Vitor Hugo B Serrão, Patrick Yip, Marine Foritano, Sandrine Barbaux, Jeffrey E Lee, Ahmed Ziyyat","doi":"10.1186/s11658-026-00984-y","DOIUrl":"https://doi.org/10.1186/s11658-026-00984-y","url":null,"abstract":"<p><strong>Background: </strong>Human fertilization requires fusion of spermatozoon and oocyte membranes to form a diploid zygote, beginning with adhesion mediated by spermatozoon IZUMO1 and oocyte JUNO. Current models propose that IZUMO1 dimerizes after interacting with JUNO, possibly triggered by a protein disulfide isomerase. It has been proposed that protein disulfide isomerase ERp57 is the trigger for IZUMO1 dimerization, a mechanism supported by parallels in viral entry, but direct evidence is lacking.</p><p><strong>Methods: </strong>In vitro fertilization studies were performed for both mice and humans using ERp57 inhibitors to confirm the importance of ERp57 in mammalian fertilization. Additionally, for this study, we generated a sperm-specific ERp57 conditional knockout mouse model and performed in vivo and in vitro fertilization experiments. Biophysical assays, including dynamic light scattering and a fluorescence-based dissociation assay, were developed and utilized to investigate interactions between ERp57 and IZUMO1. Structural modeling was used to supplement the ERp57 and IZUMO1 interaction findings.</p><p><strong>Results: </strong>Here, we reveal that ERp57 is crucial for mammalian fertilization but does not show evidence of any direct interaction with IZUMO1. ERp57 inhibition significantly reduces fertilization in human and mouse in vitro assays, and ERp57 spermatozoa conditional knockout (scKO) males exhibit severe hypofertility in vivo and in vitro. ERp57 localizes to the equatorial segment of human spermatozoa following the acrosome reaction, consistent with a role in gamete interaction. However, ERp57-deficient spermatozoa fail to accumulate in the perivitelline space, pointing to a role upstream of membrane fusion. Additionally, ERp57 neither promotes IZUMO1 dimerization nor facilitates dissociation of the IZUMO1-JUNO complex. Structural modeling predicted no significant interaction between ERp57 and IZUMO1, supporting experimental findings.</p><p><strong>Conclusions: </strong>These findings establish ERp57 as critical for mammalian fertilization but challenge existing assumptions about its mechanistic involvement in gamete membrane fusion. Our research contributions provide key new mechanistic insights that reexamine and reshape the current paradigms surrounding the fundamental process of sperm-egg fusion. By addressing a long-standing bottleneck in the field, our work opens new avenues of investigation that could finally lead to the identification of the elusive human sperm-egg fusogen.</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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}