Life sciences最新文献

{"title":"A novel immunological perspective on female-specific cancers: Exploring the signaling pathways of tertiary lymphoid structures and their clinical applications","authors":"Si-Qi Li ,&nbsp;Xiao-Ren Zhu ,&nbsp;Yuan-Yuan Liu ,&nbsp;Min-Bin Chen","doi":"10.1016/j.lfs.2025.123800","DOIUrl":"10.1016/j.lfs.2025.123800","url":null,"abstract":"<div><div>Female-specific cancers, including breast, cervical, and ovarian cancers, are significant contributors to global morbidity and mortality. Despite advancements in conventional treatment modalities, challenges such as recurrence and therapeutic resistance remain prevalent, highlighting the urgent need for novel therapeutic strategies. Tertiary lymphoid structures (TLS), which act as immune microstructures within the tumor microenvironment, have emerged as key regulators of antitumor immunity. Increasing attention has been directed toward understanding their presence and functional roles in gynecological malignancies. Effective assessment and quantification of TLS can aid in evaluating clinical outcomes for patients with gynecological cancers. Current research has focused on the mechanisms driving TLS formation, techniques for their assessment, and therapeutic strategies aimed at promoting their development. This review comprehensively examines the distribution, structural characteristics, and functional roles of TLS in female-specific cancers, emphasizing their ability to activate localized immune responses through signaling pathways such as NF-κB, STAT3, and Wnt. These pathways play key roles in regulating TLS formation, immune cell infiltration, and the modulation of antitumor immunity. This is the first review to systematically explore the interaction between TLS and hormone signaling, particularly estrogen and progesterone, within tumor microenvironments of breast and ovarian cancers. Furthermore, the clinical potential of TLS is explored, highlighting its use as a biomarker for predicting therapeutic efficacy and disease prognosis and its role in guiding novel immunotherapeutic strategies. By systematically analyzing the signaling pathways and immune regulatory mechanisms associated with TLS, this review provides a strong scientific foundation for the development of innovative immunotherapies targeting gynecological cancers.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123800"},"PeriodicalIF":5.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144243095","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":"Dapagliflozin promotes metabolic reprogramming against myocardial infarction through the MAPK-FOXO3-STC1 and HIF-1a-STC1 pathways","authors":"Xiaoliang Zhang ,&nbsp;Chunbei Zhou ,&nbsp;Guozhu Chen ,&nbsp;Yuanzhu Li ,&nbsp;Xiaorui Liu ,&nbsp;Suxin Luo","doi":"10.1016/j.lfs.2025.123798","DOIUrl":"10.1016/j.lfs.2025.123798","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial infarction (MI) results in mitochondrial dysfunction and metabolic imbalance, ultimately causing cellular injury and impaired cardiac function. Dapagliflozin (DAPA) has been shown to reduce cardiovascular mortality; however, the underlying mechanisms by which it confers cardioprotection in MI remain incompletely understood.</div></div><div><h3>Methods</h3><div>To explore the protective role of DAPA, an oxygen-glucose deprivation (OGD) model was established in H9c2 cardiomyoblasts to assess its effects on cell proliferation, apoptosis, metabolism, and mitochondrial function. A series of molecular assays, including qRT-PCR, Western blotting, chromatin immunoprecipitation (ChIP), dual-luciferase reporter analysis, and rescue experiments, were performed to elucidate the involvement of HIF-1α, FOXO3, and STC1 in DAPA-mediated responses. In vivo, the cardioprotective effects of DAPA were validated using a rat model of MI.</div></div><div><h3>Results</h3><div>DAPA promoted proliferation, inhibited apoptosis, and restored glucose uptake, ATP generation, and mitochondrial activity in OGD-treated H9c2 cells by modulating the JNK signaling pathway, promoting FOXO3 degradation, and engaging the HIF-1α–STC1 axis. In MI rats, DAPA significantly reduced infarct size, improved cardiac function, and alleviated myocardial fibrosis and apoptosis. Rescue experiments further confirmed that overexpression of STC1 potentiated DAPA's effects, whereas STC1 knockdown attenuated them.</div></div><div><h3>Conclusion</h3><div>These findings indicate that the HIF-1α–FOXO3–STC1 pathway plays a central role in the cardioprotective mechanisms of DAPA. By modulating the MAPK–FOXO3–STC1 and HIF-1α–STC1 signaling cascades, DAPA improves mitochondrial function and metabolic homeostasis, supporting its therapeutic potential in the treatment of MI.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123798"},"PeriodicalIF":5.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222388","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":"The role and mechanisms of RNA-binding proteins in the development of ovarian aging and related diseases","authors":"Wenjia Luo ,&nbsp;Chunxia Huang ,&nbsp;Ke Sun ,&nbsp;Kangping Yang ,&nbsp;Jiaqiang Wu ,&nbsp;Liang Yang","doi":"10.1016/j.lfs.2025.123792","DOIUrl":"10.1016/j.lfs.2025.123792","url":null,"abstract":"<div><div>Ovarian aging is a key factor influencing female fertility and overall health. RNA-binding proteins (RBPs) regulate mRNA stability and translation, playing a significant role in maintaining ovarian function. This review discusses RBPs' involvement in oocyte development, folliculogenesis, and ovarian homeostasis. Additionally, we explore their roles in ovarian aging-related diseases and potential strategies for mitigating ovarian decline by targeting RBP activity. This review highlights RBPs' molecular mechanisms and potential applications for understanding and treating ovarian aging.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123792"},"PeriodicalIF":5.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212988","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":"BDNF/TrkB signaling pathway and WDR neurons: Core factors inducing central sensitization of neuropathic pain","authors":"Yebei Zhong ,&nbsp;Cheng Huang","doi":"10.1016/j.lfs.2025.123796","DOIUrl":"10.1016/j.lfs.2025.123796","url":null,"abstract":"<div><div>Neuropathic pain is a complex pain syndrome resulting from damage or dis-ease affecting the somatosensory nervous system. Currently, there are no effective treatment options available, which has drawn considerable attention from researchers due to its high prevalence. The mechanisms underlying neuropathic pain are multifaceted, involving structural and functional alterations in central nervous system (CNS), pain signals transduction, and neuroinflammation, with central sensitization recognized as an important mechanism. Central sensitization is characterized by increased neuronal excitability and synaptic plasticity. Brain-derived neurotrophic factor (BDNF) plays a pivotal role in central sensitization induced by nerve injury through its binding to the tropomyosin receptor kinase B (TrkB) receptor. The activation of BDNF/TrkB signaling pathway modulates neuronal synaptic plasticity and enhances the transmission of pain signals. Additionally, the spinal dorsal horn (SDH) wide dynamic range (WDR) neurons act as integrative centers for pain signals, receiving inputs from peripheral nociceptive stimuli and exhibiting heightened excitability in neuropathic pain. Hyperexcited WDR neurons not only respond to central sensitization but also are further intensified by BDNF/TrkB signaling pathway, ultimately amplifying pain perception. This review intends to systematically summarize the interactions between central sensitization, BDNF/TrkB signaling, and WDR neurons, illustrating their potential relationships in neuropathic pain and identifying possible intervention targets, thereby offering new insights and strategies for neuropathic pain relief.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123796"},"PeriodicalIF":5.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212989","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":"ON101 counteracts oxidative stress and inflammation in radiation-induced dermatitis through Keap1/Nrf2 signaling","authors":"Yi-Chieh Tsai ,&nbsp;Ming-Shou Hsieh ,&nbsp;Iat-Hang Fong ,&nbsp;Chi-Tai Yeh ,&nbsp;Shun-Cheng Chang","doi":"10.1016/j.lfs.2025.123788","DOIUrl":"10.1016/j.lfs.2025.123788","url":null,"abstract":"<div><div>Radiation-induced dermatitis (RID) remains a significant and challenging side effect of radiotherapy, with few effective topical interventions. This study investigates ON101 as a therapeutic candidate for RID, focusing on its modulation of the Keap1/Nrf2 signaling pathway. Using a murine model of radiation-induced skin injury, topical application of ON101 substantially reduced skin damage, as evidenced by decreased wound severity scores, preserved body weight, and improved histopathological outcomes. Histological analyses using H&amp;E and Masson's trichrome staining revealed that ON101 and its active component, PA-F4, reversed radiation-associated dermal thickening and fibrosis, thus restoring skin architecture and elasticity. RNA sequencing demonstrated that ON101 treatment downregulated Keap1 expression, facilitating nuclear translocation and activation of Nrf2, a central regulator of antioxidant responses. Consistently, irradiated human keratinocytes (HaCaT) and dermal fibroblasts (HDFs) treated with ON101 exhibited significantly decreased levels of oxidative stress markers and pro-inflammatory cytokines, confirming its combined antioxidant and anti-inflammatory effects. Moreover, ON101 enhanced the expression of key genes involved in DNA damage repair and skin regeneration, including EGFR, VIM, and CTNNB1, highlighting its regenerative potential. Mechanistically, the study identified increased p62 and nuclear Nrf2 levels following ON101 treatment, confirming activation of the p62-Keap1-Nrf2 axis—a pivotal pathway governing cellular defense mechanisms against oxidative damage. Collectively, these results suggest that ON101 provides comprehensive protection against RID by modulating oxidative stress, reducing inflammation, and promoting tissue repair. Through these targeted molecular mechanisms, ON101 emerges as a promising topical therapeutic agent for managing radiation-induced cutaneous toxicity in clinical settings.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123788"},"PeriodicalIF":5.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234485","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":"STC1 promotes paclitaxel resistance in oral squamous cell carcinoma by inhibiting oxidative stress via activating the JAK/STAT signaling pathway","authors":"Xinghan Wu ,&nbsp;Hao Liu ,&nbsp;Mingfeng Li ,&nbsp;Chuanni Feng ,&nbsp;Min Liu ,&nbsp;Yanfeng Xu ,&nbsp;Yalan Lu ,&nbsp;Yanju Gong ,&nbsp;Xiaomeng Li ,&nbsp;Fan Ye ,&nbsp;Lin Jiang ,&nbsp;Yanhong Li ,&nbsp;Binbin Li ,&nbsp;Chuan Qin","doi":"10.1016/j.lfs.2025.123787","DOIUrl":"10.1016/j.lfs.2025.123787","url":null,"abstract":"<div><h3>Aims</h3><div>Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, with chemoresistance is the greatest challenge in chemotherapeutic treatment. Stanniocalcin 1 (STC1) is correlated with tumor malignancy and chemoresistance in various cancers, but its role in OSCC paclitaxel (PTX) resistance remains elusive. This study aimed to clarify STC1's impact on OSCC PTX resistance and elucidate its underlying mechanism.</div></div><div><h3>Materials and methods</h3><div>The PTX-resistant OSCC cell line CAL-27/PTX was established by stepwise exposure to increasing PTX concentrations. Transcriptomic sequencing, CCK-8 assays, western blotting, RT-qPCR, lentiviral-mediated silencing or overexpression, reactive oxygen species (ROS) detection, and ELISA were used to assess STC1 expression and function. In vivo validation was conducted using both cell line-derived (CDX) and patient-derived xenograft (PDX) models.</div></div><div><h3>Key findings</h3><div>The expression of STC1 was significantly increased in CAL-27/PTX cells and linked to cancer stem cell-like characteristics and epithelial-mesenchymal transition. Knockdown of STC1 expression suppresses tumor development. Mechanistically, STC1 activated the JAK/STAT signaling pathway, which mediated the upregulation of antioxidant genes (GPX4, FTH1, and SLC7A11) to attenuate PTX-induced oxidative stress. Additionally, STC1 promoted intercellular transfer of PTX resistance via a paracrine mechanism. In vivo, high STC1 expression mediated PTX resistance in both CDX and PDX tumor models.</div></div><div><h3>Significance</h3><div>This study identifies the STC1-STAT3-SLC7A11 axis as a key regulator of resistance to oxidative stress in OSCC, highlighting STC1 as a promising therapeutic target to overcome chemoresistance and improve outcomes in PTX-based therapies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123787"},"PeriodicalIF":5.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212986","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":"Absence of Rab39b-induced macroautophagy impairment increases neurotoxic α-synuclein and causes degeneration of substantia nigra dopaminergic neurons in mouse model of X-linked Parkinson's disease","authors":"Ching-Chi Chiu ,&nbsp;Yi-Hsin Weng ,&nbsp;Tu-Hsueh Yeh ,&nbsp;Wan-Shia Chen ,&nbsp;Shu-Yu Liu ,&nbsp;Tai-Ju Chiu ,&nbsp;Allen Hon-Lun Li ,&nbsp;Hung-Li Wang","doi":"10.1016/j.lfs.2025.123789","DOIUrl":"10.1016/j.lfs.2025.123789","url":null,"abstract":"<div><div>Deletion or mutation of RAB39B gene causes RAB39B deficiency in male patients and resulting X-linked Parkinson's disease (PD). Male Rab39b knockout (Rab39b^-/Y) mouse, which simulates PD RAB39B genetic mutation-induced absence of functional RAB39B, was prepared to study pathomechanisms of RAB39B deficiency-evoked neurodegeneration of substantia nigra (SN) dopaminergic cells. Rab39b^-/Y mice manifested PD motor impairment, degeneration of SN dopaminergic neurons and presence of SN Lewy bodies. Rab39b insufficiency caused macroautophagy impairment via reducing Atg3, Atg5, Atg7, Atg12 and Atg16L1 in SN. Rab39b deficiency-induced macroautophagy impairment upregulated α-synuclein within SN dopaminergic neurons and α-synuclein oligomers in SN. Macroautophagy activator rapamycin reversed macroautophagy dysfunction or upregulation of SN α-synuclein and ameliorated motor deficits and demise of SN dopaminergic neurons in Rab39b^-/Y mice. Rab39b paucity-promoted upregulation of ER α-synuclein activated ER stress-triggered apoptotic signaling in SN. Rab39b insufficiency increased SN mitochondrial α-synuclein and produced mitochondrial defect and oxidative stress. Rab39b deficiency-induced ER stress apoptotic signaling, mitochondrial impairment and oxidative damage activated mitochondrial pro-apoptotic pathway in SN. Rab39b deficiency-induced upregulation of α-synuclein oligomers induced excitation of SN microglia and NLRP3 inflammasome and elevation of IL-1β, IL-18 or TNF-α. Rab39b paucity-induced upregulation of pro-inflammatory cytokines activated MKK4-JNK -c-Jun/ATF-2 pro-apoptotic cascade and RIPK1-RIPK3-MLKL necroptotic pathway in SN. Our results suggest that RAB39B deficiency causes demise of SN dopaminergic neurons and X-linked PD by impairing macroautophagy and upregulating neurotoxic α-synuclein, which stimulates ER stress and mitochondrial apoptotic cascades and activates microglia and NLRP3 inflammasome. Our data also suggest that rapamycin possesses therapeutic effects on RAB39B mutation-induced X-linked PD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123789"},"PeriodicalIF":5.2,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212987","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":"ER stress-related mitochondrial protein-coding gene risk model and in vitro experiments unveil OMA1 as a novel prognostic and therapeutic biomarker for low-grade glioma","authors":"Chaoying Qin ,&nbsp;Yabo Feng ,&nbsp;Junquan Wang ,&nbsp;Weicheng Huang ,&nbsp;Liangqi Jiang ,&nbsp;Yang Li","doi":"10.1016/j.lfs.2025.123773","DOIUrl":"10.1016/j.lfs.2025.123773","url":null,"abstract":"<div><h3>Background</h3><div>Low-grade gliomas (LGG) are known for their slow growth yet retain the potential to progress to more aggressive malignancies. Glioma cells are frequently exposed to stressors such as hypoxia, nutrient deprivation, and oxidative stress, which disrupt protein folding within the endoplasmic reticulum (ER), leading to ER stress and activation of the unfolded protein response (UPR). ER stress plays a complex role in glioma initiation, progression, and resistance to chemotherapy. Dysregulated signaling between mitochondria and the ER can further exacerbate ER stress, impacting glioma cell survival and proliferation. Elucidating the molecular mechanisms by which mitochondrial interactions influence ER stress may reveal novel therapeutic targets for LGG treatment.</div></div><div><h3>Methods</h3><div>ER-stress related mitochondrial protein-coding genes (ERSMGs) linked to LGG prognosis were identified using Mitocarta3.0, Genecards, CGGA, and TCGA data. A prognostic model was developed via univariate and LASSO-Cox regression and validated by ROC curves. OMA1's role was assessed through knockdown experiments in LGG cell lines.</div></div><div><h3>Results</h3><div>Eleven ERSMGs were significantly associated with LGG prognosis. The model achieved reliable predictive accuracy (AUC &gt; 0.6) and stratified patients into high- and low-risk groups with distinct survival rates. High-risk patients exhibited increased sensitivity to SB505124. OMA1 knockdown in LGG cells induced ER stress by promoting mitochondrial fusion, increasing mtROS, ultimately inhibiting cell proliferation and invasion.</div></div><div><h3>Conclusion</h3><div>This study provides a novel prognostic model based on ERSMGs, offering novel insights into LGG progression and invasion. OMA1-mediated mitochondrial dysfunction and ER stress play critical roles in glioma cell growth and survival, representing potential therapeutic targets.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123773"},"PeriodicalIF":5.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225860","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":"Under pressure: Updated insights into the mechanisms of Leishmania's defense in response to oxidative stress","authors":"Angélica Paulina Nunes ,&nbsp;Yasmin Munhoz dos Santos-Destro ,&nbsp;Ana Carolina Jacob Rodrigues ,&nbsp;Mariana Barbosa Detoni ,&nbsp;Ellen Mayara Souza Cruz ,&nbsp;Giovana Sita Berbert ,&nbsp;Byulnim Park ,&nbsp;Maria Fernanda Maya Kuriki Pires ,&nbsp;Wander Rogério Pavanelli ,&nbsp;Maiara Voltarelli Providello","doi":"10.1016/j.lfs.2025.123779","DOIUrl":"10.1016/j.lfs.2025.123779","url":null,"abstract":"<div><div>Leishmaniasis is a disease caused by over 20 species of protozoa of the genus <em>Leishmania</em>, transmitted by the bite of infected phlebotomine sandflies. This parasitic infection has an anthropozoonotic nature, affecting both wild and domestic animals, as well as humans. It may present itself as three main clinical forms: cutaneous, mucocutaneous, or visceral leishmaniasis. The interaction between the parasite and the host's immune system is complex, involving evasion mechanisms primarily through the modulation of oxidative stress. <em>Leishmania</em> lacks several antioxidant enzymes common to mammals; instead, it relies on a few alternative redox systems, such as the trypanothione family which is essential for counteracting reactive oxygen and hydrogen species within phagolysosomes of neutrophils and macrophages. These mechanisms also modulate the composition and pH of the parasitophorous vacuole, preventing the efficient elimination of the amastigote forms from host cells. Additionally, the parasite induces cytoskeletal and metabolic changes in mammalian host cells to promote a favorable microenvironment for its survival. Given these aspects, this review discusses <em>Leishmania</em>'s oxidative stress evasion strategies, focusing on both parasite-specific adaptations and their effects on host metabolism and immune response, whether in macrophages, neutrophils, or dendritic cells; as well as the role of oxidative stress in canine visceral leishmaniasis. A deeper understanding of these mechanisms may support the development of novel therapeutic approaches, such as drugs targeting oxidative response modulation and improved vaccination strategies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123779"},"PeriodicalIF":5.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216257","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":"METTL3-mediated m6A modification of FUNDC1/IP3R2 pathway facilitates cardiac hypertrophy in obesity hypertension","authors":"Yulong Ma ,&nbsp;Da Li ,&nbsp;Xunjie Zhou,&nbsp;Xiaozhe Chen,&nbsp;Chunlei Hou,&nbsp;Yunfeng Li,&nbsp;Yuxiu Zhao,&nbsp;Mingtai Gui,&nbsp;Lei Yao,&nbsp;Jianhua Li,&nbsp;Mingzhu Wang,&nbsp;Deyu Fu,&nbsp;Bo Lu","doi":"10.1016/j.lfs.2025.123780","DOIUrl":"10.1016/j.lfs.2025.123780","url":null,"abstract":"<div><h3>Background</h3><div>FUNDC1-mediated mitochondria-associated endoplasmic reticulum membrane (MAM) Ca²⁺ conduction is crucial in cardiac hypertrophy. N6-methyladenosine (m6A) methylation, a crucial mRNA modification, is implicated in this process. We hypothesise that m6A regulation of FUNDC1-mediated MAM-associated Ca²⁺ overload contributes to obesity hypertension (OBH) cardiac hypertrophy.</div></div><div><h3>Methods</h3><div>We investigated OBH in spontaneously hypertensive rats fed a high-fat diet, with WKY rats as controls. Assessments included blood pressure, cardiac hypertrophy, pyroptosis, protein expression of MAM-related (FUNDC1, IP3R2) and m6A-related gene (METTL3, IGF2BP2). MeRIP assay detected m6A methylation in mRNA. We also examined cardiomyocyte morphology, viability, mitochondrial function (mtROS, SOD, MDA and ATP levels), and expression of pyroptosis-related factors (IL-1β, IL-18, NLRP3, GSDMD-N and Caspase-1/p10) in vitro. Silencing and overexpression of FUNDC1 and METTL3 clarified MAM effects on cardiac hypertrophy. FUNDC1 and IP3R2 interaction was assessed by co-immunoprecipitation.</div></div><div><h3>Results</h3><div>OBH rats exhibited significantly elevated blood pressure, cardiac hypertrophy, MAM dysfunction, elevated FUNDC1, IP3R2 and METTL3 expression, and pyroptosis. Ang II treatment in vitro upregulated FUNDC1, causing mitochondrial dysfunction, inflammation and pyroptosis in cardiomyocytes. FUNDC1 knockdown improved cardiomyocyte morphology and function, reduced mitochondrial Ca²⁺ concentration, enhanced mitochondrial function and attenuated pyroptosis while increasing IP3R2 ubiquitination. Mito Tempo reversed cardiomyocyte hypertrophy, mitochondrial dysfunction, inflammatory response and pyroptosis induced by FUNDC1 overexpression. Additionally silencing METTL3 and IGF2BP2 reduced m6A methylation of FUNDC1, inhibiting its expression.</div></div><div><h3>Conclusion</h3><div>METTL3 regulates FUNDC1 m6A methylation modification via IGF2BP2, thereby affecting FUNDC1 expression. FUNDC1 binding to IP3R2 regulates MAM-associated Ca²⁺ overload, inducing mitochondrial dysfunction and pyroptosis, leading to cardiac hypertrophy in OBH.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"377 ","pages":"Article 123780"},"PeriodicalIF":5.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199524","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}