Life sciences最新文献

{"title":"Age-progressive stratification of Becker muscular dystrophy patients: a focus on muscle biopsy fibrosis, inflammation and capillary network","authors":"Simona Zanotti ,&nbsp;Patrizia Ciscato ,&nbsp;Laura Napoli ,&nbsp;Letizia Bertolasi ,&nbsp;Stefania Corti ,&nbsp;Giacomo Pietro Comi ,&nbsp;Maurizio Moggio ,&nbsp;Monica Sciacco ,&nbsp;Michela Ripolone","doi":"10.1016/j.lfs.2025.123676","DOIUrl":"10.1016/j.lfs.2025.123676","url":null,"abstract":"<div><div>Skeletal muscle dystrophies comprise a group of inherited disorders characterized by progressive muscle weakness, with Duchenne and Becker muscular dystrophies (DMD/BMD) being among the most severe. These dystrophies are caused by mutations in the <em>dystrophin</em> gene, resulting in muscle cell instability, chronic inflammation, fibrosis, and impaired muscle regeneration. Although skeletal muscle has intrinsic regenerative potential via satellite cells, the ongoing muscle damage in DMD/BMD depletes these cells and promotes fibrosis. Inflammation also plays a pivotal role, with immune cell infiltration correlating with disease severity.</div><div>This study investigates fibrosis, inflammation, and capillarization in BMD patients across different age groups to clarify how disease progression varies over time. Morphological analyses of muscle biopsies revealed an increase in connective tissue, particularly in adult patients. Pediatric patients showed reduced capillarization, whereas adult patients displayed vascular adaptations, including elevated capillary-to-fibre ratios and capillary contacts, indicative of compensatory mechanisms in response to chronic muscle degeneration.</div><div>Inflammatory profiles also varied with age: younger adult patients exhibited a predominance of CD68-positive macrophages, while older adults demonstrated increased CD4/CD8 T-cell activity.</div><div>Our findings highlight pronounced age-dependent differences in muscle pathology, encompassing structural adaptations, fibrosis, and inflammation, which may be crucial for developing age-tailored therapeutic approaches.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123676"},"PeriodicalIF":5.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D3, cholecalciferol via its hydroxylmetabolites, receptors and metabolizing enzymes modulates male reproductive functions","authors":"David Tolulope Oluwole ,&nbsp;Ayodeji Folorunsho Ajayi","doi":"10.1016/j.lfs.2025.123680","DOIUrl":"10.1016/j.lfs.2025.123680","url":null,"abstract":"<div><div>Although biologically known for its central role in calcium homeostasis, Vitamin D3 (VD3), owing to its scattered receptors across bodily tissues and the presence of its metabolizing enzymes, has recently garnered scientific attention. This review examined the literature to document the role and specific mechanisms of action of VD3, its receptors, and metabolizing enzymes in male reproduction. Using the keywords Vitamin D3, vitamin D receptors, vitamin D metabolic enzymes, and male reproductive system to search PUBMED and other academic archives, it was observed that VD3, through its interaction with the VDR and with the backing of the activities of its metabolizing enzymes, modulates the male reproductive functions, acting as an antioxidant and anti-inflammatory in reproductive organs to prevent oxidative damages that may result from exposure to environmental toxicants and the increased oxygen utilization by mitochondria owing to high level of unsaturated fatty acids in the testis, thus preventing male infertility.</div></div><div><h3>Essential points</h3><div><ul><li><span>a)</span><span><div>Vitamin D₃, interaction with its receptor and metabolizing enzymes modulates the male reproductive functions</div></span></li><li><span>b)</span><span><div>Damages to reproductive organs result from mitochondrial oxygen utilization, high level of unsaturated fatty acids and environmental toxicants,</div></span></li><li><span>c)</span><span><div>Vitamin D3 modulates spermatogenesis by upregulating enzymes responsible for testicular androgen hormone production</div></span></li><li><span>d)</span><span><div>Vitamin D3 acts as antioxidant and anti-inflammatory agent in reproductive organs to prevent organ damages</div></span></li></ul></div><div><strong>Search Strategy</strong>: PUBMED, GOOGLE SCHOLAR, MEDLINE, SCOPUS database</div><div>This review narrated the impact of VD3 on male reproduction: exploring its Receptor-Mediated and Enzymatic Regulation of Fertility, Erectile Function, Testicular Health, and Sperm Quality. Articles used were obtained from PubMed, MEDLINE, and Scopus databases with the Subject title terms “Vitamin D3” OR “Cholecalciferol” OR “1, 25-Dihydroxyvitamin D3” AND “Male fertility” OR “Erectile function” OR “Testicular health” OR “Sperm quality”, “Vitamin D3” OR “VD3” AND “Vitamin D receptor” OR “VDR” AND “Male reproductive health” OR “Fertility”. “1, 25-Dihydroxyvitamin D3” OR “1-alpha-hydroxylase” AND “Testicular function” OR “Sperm motility” OR “Sperm morphology”. “Vitamin D3” OR “VD3” AND “CYP27B1” OR “CYP24A1” AND “Male reproductive biology” OR “Fertility”. Articles published in English language were used.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123680"},"PeriodicalIF":5.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway","authors":"Siyu Lin ,&nbsp;Zhiyu Ji ,&nbsp;Jie Gao ,&nbsp;Jiawei Fan ,&nbsp;Jingjing Hou ,&nbsp;Sha Liu ,&nbsp;Chuanxi Wang ,&nbsp;Keyang Chen ,&nbsp;Liming Tao ,&nbsp;Zhengxuan Jiang","doi":"10.1016/j.lfs.2025.123681","DOIUrl":"10.1016/j.lfs.2025.123681","url":null,"abstract":"<div><h3>Background and aim</h3><div>Inflammation is a crucial aspect of the pathophysiology of diabetic retinopathy (DR). Polymerase delta-interacting protein 2 (Poldip2) has been linked to inflammation in various disorders, but its role in DR remains unclear. This study aims to elucidate the underlying mechanisms of Poldip2 in DR.</div></div><div><h3>Methods</h3><div>Transmission Electron Microscopy (TEM) revealed significant mitophagy reduction due to the accumulation of damaged mitochondria in the retinas of Streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rats. In vivo, AAV9-<em>Poldip2</em>-shRNA was administered to STZ-induced DR rats, partially restoring mitophagy. Microglia (BV2) cells cultured in high glucose (HG) conditions exhibited similar behavior. Likewise, BV2 received <em>Poldip2</em>-siRNA treatment to further explore the regulatory mechanism of Poldip2.</div></div><div><h3>Results</h3><div>In vivo, Poldip2 was significantly elevated alongside VEGFR and SQSTM1/P62, while mitophagy markers were inhibited. Under HG conditions, BV2 secret large amounts of pro-inflammatory factors. Human Retinal Microvascular Endothelial Cells (HRMECs) were significantly affected by these HG-cultured BV2, leading to angiogenesis. Notably, Poldip2 knockdown significantly increased Pink1 by preventing its ubiquitination-mediated degradation, thereby enhancing mitophagy and reducing retinal inflammation.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that Poldip2 contributes to DR by promoting Pink1 degradation, which inhibits mitophagy and leads to inflammation. Targeting Poldip2 may offer a novel therapeutic strategy for DR.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123681"},"PeriodicalIF":5.2,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Indole-3-lactic acid derived from tryptophan metabolism alleviates the sFlt-1-induced preeclampsia-like phenotype via the activation of aryl hydrocarbon receptor” [Life Sci. 361 (2025) 123329]","authors":"Yingying Wei ,&nbsp;Haojun Tian ,&nbsp;Hao Peng ,&nbsp;Ayinisa Wubulikasimu ,&nbsp;Mengtian Wei ,&nbsp;Han Li ,&nbsp;Qizhi He ,&nbsp;Tao Duan ,&nbsp;Yiying Huang ,&nbsp;Kai Wang","doi":"10.1016/j.lfs.2025.123666","DOIUrl":"10.1016/j.lfs.2025.123666","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123666"},"PeriodicalIF":5.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-mediated muscle-hypothalamus crosstalk: Improvement for cognitive dysfunction caused by disrupted circadian rhythm","authors":"Jun-xiao Shi ,&nbsp;Zi-yuan Wang ,&nbsp;Sheng-wen Wang ,&nbsp;Qi Shen ,&nbsp;Xing Tan","doi":"10.1016/j.lfs.2025.123657","DOIUrl":"10.1016/j.lfs.2025.123657","url":null,"abstract":"<div><div>In contemporary societal evolution, the increasing disruption of the natural sleep-wake cycle, attributable to factors such as shift work and overexposure to artificial light, has been paralleled by a marked escalation in the incidence of cognitive impairments and the prevalence of neurodegenerative diseases. Current management strategies for cognitive impairments include pharmacological and non-pharmacological interventions. Pharmacological interventions for cognitive impairments typically involve medications to manage cognitive symptoms and improve neurological functions. However, these drugs show limited long-term efficacy in slowing disease progression and may cause side effects. Given the widespread occurrence of cognitive dysfunction, it is crucial to develop accessible non-pharmacological interventions. Physical activity and exercise have emerged as pivotal lifestyle determinants known to exert a modulatory effect on the risk profile for cognitive dysfunction caused by disrupted circadian rhythms. The skeletal muscle, a dynamic tissue, undergoes a profound morphological and metabolic reconfiguration in response to physical exertion, along with the secretion of myokines. Additionally, the hypothalamus, particularly the ventromedial nuclei, arcuate nuclei, and the suprachiasmatic nucleus, have crucial functions in regulating physical activity, influencing energy metabolism, and managing circadian cycles. Nevertheless, the communication between the hypothalamus and skeletal muscle during exercise is not fully understood. This narrative review integrates current knowledge on the interaction between the hypothalamus and skeletal muscle during exercise, emphasizing its neuroendocrine effects and potential therapeutic implications for alleviating cognitive dysfunction associated with disrupted circadian rhythms.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123657"},"PeriodicalIF":5.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bexarotene regulates zebrafish embryonic development by activating Wnt signaling pathway","authors":"Wenwen Zha ,&nbsp;Ziang Wang ,&nbsp;Weitao Hu ,&nbsp;Chenkai Ge ,&nbsp;Wenbin Yuan ,&nbsp;Qinyuan Shen ,&nbsp;Weirong Li ,&nbsp;Wanqing Chen ,&nbsp;Jingrong Tang ,&nbsp;Zhonghao Xiao ,&nbsp;Yunlong Meng ,&nbsp;Lirong Huang ,&nbsp;Zilin Zhong ,&nbsp;Tao-Sheng Li ,&nbsp;Jianjun Chen ,&nbsp;Zigang Cao","doi":"10.1016/j.lfs.2025.123664","DOIUrl":"10.1016/j.lfs.2025.123664","url":null,"abstract":"<div><div>Bexarotene (Bex) is a selective retinoid X receptor (RXR) agonist and is commonly used as an anti-tumor drug in the clinic to treat patients with cutaneous T-cell lymphoma (CTCL). With the widespread use of this drug, people are increasingly concerned about its side effects and safety of use. At present, the effects of bexarotene drugs on the health of organisms remain uncertain, but retinoid drugs are generally biologically active and may pose potential risks to them. Therefore, in this study, we used a zebrafish model to evaluate the effects of Bex on embryonic development. Six hours after fertilization, we exposed zebrafish embryos to 3 μg/L, 6 μg/L, and 9 μg/L bexarotene. At 96 hpf, compared with the control group, zebrafish embryos exposed to bexarotene showed obvious heart and liver development defects, including reduced hatching rate, pericardial enlargement, heart rate disorder, yolk sac edema, small liver area and abnormal photo-optical motor responses. Transcriptome and qPCR results showed abnormal expression of genes related to heart and liver development was induced by Bexarotene. Mechanistically, bexarotene induced a significant upregulation of the transcriptional expression levels of genes related to the Wnt signaling pathway, and IWR-1 was able to effectively rescue the heart and liver developmental defects of zebrafish caused by bexarotene. Therefore, our study showed that bexarotene may cause zebrafish embryonic developmental defects by upregulating the Wnt signaling pathway, revealing the side effects and associated novel mechanisms of bexarotene, and providing a theoretical basis for its safe and effective use in the treatment of clinically related diseases.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123664"},"PeriodicalIF":5.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic insights into metabolic dysfunction-associated steatotic disease: Identifying therapeutic targets and assessing on-target side effects","authors":"Luojia Dai ,&nbsp;Zhenqiu Liu ,&nbsp;Chengnan Guo ,&nbsp;Hong Fan ,&nbsp;Chengjun Zhang ,&nbsp;Jiayi Huang ,&nbsp;Xin Zhang ,&nbsp;Shuzhen Zhao ,&nbsp;Haili Wang ,&nbsp;Tiejun Zhang","doi":"10.1016/j.lfs.2025.123665","DOIUrl":"10.1016/j.lfs.2025.123665","url":null,"abstract":"<div><h3>Aims</h3><div>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, yet treatment options remain inadequate. To uncover new therapeutic targets for MASLD, we conducted a comprehensive proteome-wide Mendelian randomization (MR) and phenome-wide association study (PheWAS).</div></div><div><h3>Materials and methods</h3><div>Discovery MR utilized protein quantitative trait loci (pQTL) data on 4907 plasma protein levels from 35,559 individuals, alongside genome-wide association study (GWAS) on MASLD from the Million Veteran Program (68,725 cases / 95,482 controls). Validation comprised five pairwise combinations of these discovery datasets with three additional datasets: pQTL data for 2923 proteins from the UK Biobank, and liver biopsy-confirmed MASLD GWAS (1483 cases/17,781 controls) and MRI-liver fat GWAS (31,377 subjects) (excluding discovery pair). Candidate proteins underwent druggability assessment and on-target side effect evaluation via PheWAS.</div></div><div><h3>Key findings</h3><div>We identified 26 proteins associated with MASLD after Bonferroni correction (<em>P</em> &lt; 1.16 × 10^-5), with 19 of them showing no significant reverse association. Interleukin-6 (IL-6), alpha-1-antitrypsin (α1-antitrypsin), 5-hydroxytryptamine receptor 7 (5-HT7R), ephrin-B1 (EFNB1), and protein MENT (CA056) were replicated. Notably, IL-6 (OR = 2.02; 95 % CI 1.54-2.64), 5-HT7R (OR = 2.73; 95 % CI 1.96-3.80), and EFNB1 (OR = 1.82; 95 % CI 1.59-2.08) were positively associated with MASLD risk, whereas α1-antitrypsin (OR = 0.84; 95 % CI 0.78-0.90) and CA056 (OR = 0.90; 95 % CI 0.86-0.94) appeared protective. Among these, IL-6, 5-HT7R, and α1-antitrypsin were druggable. PheWAS identified potential cardiovascular side effects for 5-HT7R and α1-antitrypsin.</div></div><div><h3>Significance</h3><div>The integrative study identified several plasma proteins associated with MASLD<em>.</em> IL-6, α1-antitrypsin, 5-HT7R, EFNB1 and CA056 deserve further investigation as potential drug targets for MASLD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123665"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAF1 promotes the progression of Helicobacter pylori-associated gastric cancer through EGFR/STAT/OAS signalling","authors":"Minglin Zhang ,&nbsp;Lingzhi Yuan ,&nbsp;Xueer Yang ,&nbsp;Xuelin Zhao ,&nbsp;Jie Xie ,&nbsp;Xiaoming Liu ,&nbsp;Fen Wang","doi":"10.1016/j.lfs.2025.123656","DOIUrl":"10.1016/j.lfs.2025.123656","url":null,"abstract":"<div><h3>Aims</h3><div><em>Helicobacter pylori (H. pylori</em>) is associated with various gastric diseases and is one of the pathogenic factors of gastric cancer (GC). We found that <em>H. pylori</em> induce the expression of TRAF1, but its mechanism of action is still unclear. Therefore, we wanted to determine whether TRAF1 is involved in the mechanism of <em>H. pylori</em>-related GC progression.</div></div><div><h3>Materials and methods</h3><div>In this study, we analysed TRAF1 expression and its prognostic significance using clinical specimens, performed functional studies involving TRAF1 overexpression or knockdown in cellular models, identified downstream signalling pathways regulated <em>via</em> RNA-seq, validated these mechanisms through pathway blockade and rescue experiments, and further confirmed the findings in an <em>H. pylori</em>-infected gastritis mouse model.</div></div><div><h3>Key findings</h3><div>TRAF1 expression was significantly elevated in GC tissues and served as a poor prognostic biomarker. TRAF1 promoted GC cell proliferation, migration and invasion. RNA-seq analysis revealed that TRAF1 activated the EGFR/STAT/OAS signalling axis, upregulated STAT3 expression and increased the transcription of the OAS gene family. Pharmacological inhibition with ruxolitinib and AG490 effectively blocked EGFR/STAT/OAS signalling. In <em>H. pylori</em>-treated cell models, <em>H. pylori</em> infection activated the EGFR/STAT/OAS signalling axis. <em>In vivo,</em> we established an <em>H. pylori</em>-induced gastritis mouse model to validate the activation of this signalling pathway during the gastritis–carcinoma transition.</div></div><div><h3>Significance</h3><div>TRAF1 may promote the proliferation, migration and invasion of <em>H. pylori</em>-associated GC by activating the EGFR/STAT/OAS signalling axis, suggesting that TRAF1 is a promising novel prognostic biomarker and therapeutic target for this malignancy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123656"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to “Epicardial adipose tissue and cardiac lipotoxicity: A review” [Life Sciences 328 (2023) 121913]","authors":"Anirban Goutam Mukherjee ,&nbsp;Kaviyarasi Renu ,&nbsp;Abilash Valsala Gopalakrishnan ,&nbsp;Rama Jayaraj ,&nbsp;Abhijit Dey ,&nbsp;Balachandar Vellingiri ,&nbsp;Raja Ganesan","doi":"10.1016/j.lfs.2025.123630","DOIUrl":"10.1016/j.lfs.2025.123630","url":null,"abstract":"","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"372 ","pages":"Article 123630"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance","authors":"Linlin Li ,&nbsp;Jialin Zhang ,&nbsp;Huiqing Li ,&nbsp;Liying Qin ,&nbsp;Han Wu ,&nbsp;Zijiao Li ,&nbsp;Lei Cai ,&nbsp;Di Chen ,&nbsp;Jianping Yang ,&nbsp;Yibing Chen ,&nbsp;Ya Xie","doi":"10.1016/j.lfs.2025.123663","DOIUrl":"10.1016/j.lfs.2025.123663","url":null,"abstract":"<div><h3>Aims</h3><div>We explored JMJD2C’s role in platinum resistance in ovarian cancer and its modulation by metformin to propose strategies for overcoming treatment limitations.</div></div><div><h3>Materials and methods</h3><div>JMJD2C and MALAT1 expression was assessed via RT-qPCR, western blotting, and immunohistochemical assays using OC cell lines, tissue from OC patients, and xenograft treatment with or without metformin. CCK-8 assays, flow cytometry, inductively coupled plasma mass spectrometry, luciferase reporter assays, and ChIP assays were employed to evaluate the impact of JMJD2C/MALAT1 on PR and the effects of metformin on JMJD2C. The effects of metformin in combination with JMJD2C knockdown were assessed in vitro and in vivo.</div></div><div><h3>Key findings</h3><div>JMJD2C and MALAT1 expression was higher in tissue samples from platinum-resistant phase compared to those from paired platinum-sensitive phase. JMJD2C upregulated MALAT1 in platinum-resistant ovarian cancer (PROC) cells by demethylating its promoter at sites H3K9m3 and H3K36m3. Overexpression of JMJD2C or MALAT1 promoted PR by activating NF-κB/P-gp and P38 MAPK/ERCC1 signaling pathways, with their knockdown produced the opposite effect. Metformin increased JMJD2C expression in tumor tissue, cell lines, and a xenograft model of OC; however, elevated JMJD2C expression attenuated the PR-reversal efficacy of low-concentration metformin. Low-dose metformin combined with JMJD2C-knockdown effectively reversed PR both in in vitro and in vivo, achieving better results than either treatment alone.</div></div><div><h3>Significance</h3><div>JMJD2C drives PR in OC by demethylating the MALAT1 promoter. Metformin upregulated JMJD2C expression, thus necessitating a higher effective dosage of metformin. Targeted inhibition of JMJD2C synergistically enhanced the efficacy of low-dose metformin in overcoming PR, thus providing a promising approach for addressing PR.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123663"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}