Cellular & Molecular Biology Letters最新文献

{"title":"Therapeutic potential of 20-Hydroxyecdysone in pulmonary arterial hypertension: involvement of Mas receptor and PI3K-Akt pathway.","authors":"Tong Lu, Weiwei Jia, Yuefei Wang, Yong Ma, Chengrun Song, Fengxia Du, Hengyu Gao, Xiangguo Jin, Hong Li, Chen Liu, Haifeng Jin, Yan Lin","doi":"10.1186/s11658-026-00880-5","DOIUrl":"10.1186/s11658-026-00880-5","url":null,"abstract":"<p><strong>Background: </strong>20-Hydroxyecdysone (20E), a natural polyhydroxylated steroid found in various edible plants, exhibits diverse pharmacological effects. Pulmonary arterial hypertension (PAH) remains challenging to treat owing to its multifactorial pathogenesis. Although recent advances, including US Food and Drug Administration (FDA)-approved therapies such as sotatercept, have improved outcomes, no curative treatment is currently available. This study aims to investigate the preventive and therapeutic effects of 20E on PAH and elucidate its underlying molecular mechanisms.</p><p><strong>Methods: </strong>A monocrotaline-induced PAH rat model was utilized to evaluate the efficacy of 20E. The Mas receptor antagonist A779 and agonist AVE0991 were used to investigate the role of Mas in PAH progression and 20E-mediated prevention. Molecular docking and pull-down assays were conducted to confirm the interaction between 20E and the Mas receptor. In vitro, the effects of 20E on Ang II-induced proliferation and migration of human pulmonary arterial smooth muscle cells (HPASMCs) were assessed. The PI3K-Akt signaling pathway was analyzed by western blot.</p><p><strong>Results: </strong>20E prevented PAH at 30 mg/kg and 90 mg/kg, while 90 mg/kg rescued preexisting PAH. The protective effects of 20E were attenuated by A779. 20E upregulated Mas receptor expression and directly bound to it. In vitro, 20E inhibited Ang II-induced HPASMC proliferation and migration. It also downregulated p-PI3K, p-Akt, and p-mTOR while restoring P27 and P21 expression. Furthermore, knockdown of the Mas in HPASMCs abolished the effects of 20E on these processes.</p><p><strong>Conclusions: </strong>20E inhibits PASMC proliferation and migration through Mas-dependent mechanisms and modulation of downstream PI3K-Akt signaling, thereby effectively preventing and rescuing PAH. It may be a promising pharmacological candidate for PAH treatment.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509766","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":"Ash2l deficiency impairs adipose tissue thermogenesis and exacerbates obesity in mice.","authors":"Yajie Hu, Jialin Zhao, Chenxi Xiao, Jiayao Liu, Jie Xu, Shenhan Xu, Wen Zhong, Ruoxue Chen, Mengting He, Chunxiang Fan, Jun Chang, Xinhua Liu","doi":"10.1186/s11658-026-00892-1","DOIUrl":"10.1186/s11658-026-00892-1","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic regulation plays a pivotal role in adipocyte development and thermogenesis. Ash2l, a key component of the COMPASS (Complex of Proteins Associated with Set1) histone methyltransferase, regulates gene expression through epigenetic mechanisms. This study explored the role of Ash2l in adipose tissue thermogenesis and obesity-related metabolic dysfunction.</p><p><strong>Methods: </strong>Ash2l was initially identified through transcriptomic analysis, and its expression was further validated in mouse models of high-fat diet (HFD), cold exposure, and CL316,243 stimulation. In vitro gain- and loss-of-function experiments were conducted to assess the role of Ash2l in adipogenesis and thermogenesis. To knockdown Ash2l in vivo, adeno-associated viruses carrying short hairpin RNA targeting Ash2l (AAV-shAsh2l) were injected into either the brown adipose tissue (BAT) or the inguinal white adipose tissue (iWAT). The functional consequences of Ash2l deficiency were evaluated in mice under room temperature, cold exposure, and HFD conditions. Finally, chromatin immunoprecipitation sequencing (ChIP-seq) was employed as an exploratory analysis to identify genomic regions associated with Ash2l during adipocyte development.</p><p><strong>Results: </strong>Our findings demonstrate that Ash2l modulates the expression of both adipogenic and thermogenic genes in adipocytes. Mice with BAT- or iWAT-knockdown of Ash2l displayed defective cold-induced thermogenesis, aggravated diet-induced obesity, and systemic metabolic dysregulation. Moreover, Ash2l knockdown in BAT under cold exposure or HFD conditions also attenuated thermogenic activity in iWAT, an effect that may be mediated by reduced secretion of FABP4.</p><p><strong>Conclusions: </strong>These findings establish Ash2l as a critical regulator of adipogenesis and thermogenesis. This study provides important insights into the epigenetic role of Ash2l in maintaining metabolic homeostasis under conditions of nutritional excess.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13045091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503302","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":"Macrophage-derived legumain ameliorates excessive mechanical stress-induced ferroptosis of nucleus pulposus cells and intervertebral disc degeneration via integrin αvβ3-Hippo signaling.","authors":"Peiyang Wang, Zhiyang Xie, Liting Deng, Yan Zhou, Zhengyuan Xu, Jiawei Gao, Rui Sun, Lei Liu, Zhiwei Wang, Xiaotao Wu, Guanrui Ren, Cong Zhang, Yuntao Wang","doi":"10.1186/s11658-026-00901-3","DOIUrl":"10.1186/s11658-026-00901-3","url":null,"abstract":"<p><p>BACKGROUND: Excessive mechanical stress is a major cause of intervertebral disc degeneration (IVDD). Macrophages can sense physical signals, but their role in responding to mechanical stress within the disc to maintain homeostasis is unclear. This study investigates the function of macrophage-derived legumain (LGMN) in IVDD. METHODS: Single-cell RNA sequencing data of human disc samples were analyzed. Macrophage-specific Lgmn knockout (LgmnF/F;LysMCre) and nucleus pulposus cell (NPC)-specific Yap1 knockin (Yap1LSL/LSL; Col2a1Cre) mice were generated to study IVDD progression in vivo using a lumbar spine instability model. In vitro, NPCs and macrophages were cultured under mechanical compression. Molecular interactions were predicted with AlphaFold3 and validated by coimmunoprecipitation and mass spectrometry. Signaling pathways were analyzed via RNA sequencing, western blot, and chromatin immunoprecipitation. Engineered LGMN-overexpressing small extracellular vesicles (sEVs) were tested therapeutically in a rat compression model. RESULTS: LGMN was significantly upregulated in human and animal degenerate discs, primarily in macrophages. Conditional knockout in macrophages accelerated IVDD in mice. Mechanistically, macrophage-derived LGMN bound to integrin αvβ3 on NPCs, inhibiting RhoA activity and activating the Hippo pathway. This led to phosphorylation and cytoplasmic retention of YAP1, which suppressed mechanical stress-induced ferroptosis in NPCs. Mechanical stress promoted STAT3 nuclear translocation in macrophages, directly enhancing LGMN transcription. Intradiscal delivery of LGMN-enriched sEVs alleviated IVDD in rats. CONCLUSIONS: Macrophage-derived LGMN is a key mechanosensitive regulator that ameliorates IVDD by inhibiting NPC ferroptosis via the integrin αvβ3–Hippo pathway, revealing a novel endogenous protective mechanism and a potential therapeutic strategy. </p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503293","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":"Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.","authors":"Sijia Hao, Yulu Guo, Qiaozhen Huang, Lu Gan, Cheng Chen, Qiang Li, Cuixia Di, Jing Si","doi":"10.1186/s11658-026-00895-y","DOIUrl":"10.1186/s11658-026-00895-y","url":null,"abstract":"<p><p>Dormant cancer cells are a significant source of cancer recurrence and metastasis and exhibit robust resistance to conventional therapies. Therefore, the exploration of novel therapeutic strategies to eliminate these cells has become a hot topic in cancer research. Ferroptosis, a newly identified form of regulated cell death, has garnered considerable attention in the field of cancer therapy in recent years. As a novel form of regulated cell death, the core mechanism of ferroptosis lies in the accumulation of intracellular iron and the induction of lipid peroxidation. Oxidative stress, the transforming growth factor-β (TGF-β) signaling pathway, autophagy, and lipid metabolism play dual roles in the survival of dormant cancer cells and the process of ferroptosis, influencing the response of dormant cancer cells to ferroptosis. These complex molecular mechanisms form a regulatory network between ferroptosis and dormant cancer cells, which holds significant implications for the development of future anti-tumor therapeutic strategies. This review synthesizes current evidence on targeting ferroptosis to eliminate dormant cancer cells, positions ferroptosis as a precision modality against dormant cancer cells, and discusses its therapeutic promise as a conceptual framework for developing next-generation anti-tumor strategies.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490408","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":"Intermittent fasting inhibits ferroptosis by modulating CD36 and its palmitoylation to alleviate diabetic dry eye.","authors":"Wenhui Wang, Jianwen Xue, Bing Xiao, Xiaobing Qian, Jing Li, Xingyan Lin, Ziyan Chen, Wei Wang, Lingyi Liang","doi":"10.1186/s11658-026-00893-0","DOIUrl":"10.1186/s11658-026-00893-0","url":null,"abstract":"<p><p>BACKGROUND: Excessive lipid accumulation in the lacrimal glands under diabetic conditions can lead to lacrimal gland dysfunction and reduced tear secretion, subsequently resulting in ocular surface inflammation, dry eye syndrome, and corneal vulnerability, ultimately compromising the patient’s quality of life. There are limited and easily implemented intervention strategies to reduce excessive lipid accumulation. While intermittent fasting (IF) has emerged as a promising metabolic intervention, its mechanistic underpinnings and therapeutic potential in diabetes-associated lacrimal gland disorders require systematic elucidation. METHODS: Diabetic mice were divided into three groups for an 8-week dietary intervention: ad libitum, meal feeding, and every-other-day feeding. After dietary intervention, we assessed the damage to lacrimal glands and ocular surface, and elucidated lipid accumulation, ferroptosis, and functional changes in the lacrimal glands. Transcriptomic analysis was used to examine gene expression. CD36 and its palmitoylation were examined around three groups. In addition, damage to the ocular surface and lacrimal glands was assessed in vivo, after the mice were injected with the ferroptosis inhibitor Fer-1 and CD36 shRNA. RESULTS: In this study, we found that compared with caloric restriction, IF more effectively reduced lipid accumulation in the lacrimal glands of diabetic db/db mice, decreased lipid peroxidation and ferroptosis, and improved function. IF downregulated CD36 expression and its palmitoylation, potentially mediated by ZDHHC20. CD36 shRNA and ferroptosis inhibition (Fer-1) comparably restored lacrimal secretory function, yet only CD36 knockdown concurrently resolved lipidostasis and ferroptosis. CONCLUSIONS: This analysis identifies CD36 as a key regulator bridging lipotoxic stress and ferroptotic execution in diabetic lacrimal gland dysfunction. Importantly, our findings suggest that ferroptosis may serve as the critical effector mechanism converting metabolic overload to glandular dysfunction, suggesting potential therapeutic value in dual targeting of lipidostasis and cell death pathways. SIGNIFICANCE: Intermittent fasting, which appears more effective than that of caloric restriction, may be associated with reduced lipid absorption resulting from decreased CD36 expression and its palmitoylation on lacrimal gland cell membranes. These findings uncover a potential novel treatment strategy for diabetic dry eye. </p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490458","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":"Combination of Tripterygium glycosides and Lactobacillus paracasei sensitises epithelial ovarian cancer to cisplatin via downregulating Keap1-Nrf2-GPX4 signalling pathway.","authors":"Meiyun Tian, Xiangdi Zeng, Yanying Zhong, Bo Ma, Ying Feng, Xiaoyun Wu, Yajie Liao, Yunyun Xu, Tingtao Chen, Buzhen Tan","doi":"10.1186/s11658-025-00850-3","DOIUrl":"10.1186/s11658-025-00850-3","url":null,"abstract":"<p><strong>Background: </strong>Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies suggest that Tripterygium glycosides (TG), derived from Tripterygium wilfordii, may enhance EOC chemo-sensitivity to DDP, potentially involving gut microbiota, though the underlying mechanisms remain to be fully elucidated.</p><p><strong>Purpose: </strong>This study sought to determine how TG enhanced chemotherapy sensitivity in EOC and to examine the involvement of gut microbiota in this process.</p><p><strong>Study design: </strong>Experimental research in vivo models was conducted, including fecal microbiota transplantation (FMT) from healthy controls and validation assays with Lactobacillus paracasei.</p><p><strong>Methods: </strong>TG were administered alone or combined with FMT to evaluate their impact on DDP sensitivity in EOC. Mechanistic studies focused on the Keap1-Nrf2-GPX4 signalling pathway and ferroptosis induction. L. paracasei was co-administered with TG to assess synergistic effects, while Nrf2 pathway activation was tested to confirm its regulatory role.</p><p><strong>Results: </strong>TG significantly enhanced DDP sensitivity in EOC, either alone or synergistically with FMT. Mechanistically, TG inhibited the Keap1-Nrf2-GPX4 axis, inducing tumor ferroptosis. Gut microbiota, particularly the probiotic Lactobacillus, contributed to this effect: L. paracasei combined with TG amplified DDP cytotoxicity in EOC cells. Conversely, Nrf2 pathway activation attenuated the synergistic effect.</p><p><strong>Conclusion: </strong>TG sensitises EOC to DDP by suppressing the Keap1-Nrf2-GPX4 pathway to trigger ferroptosis, with gut microbiota (e.g., L. paracasei) playing a synergistic role. Combining TG and probiotics may offer a promising and innovative method to improve chemotherapy efficacy in EOC, offering a foundation for future therapeutic development.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147490426","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":"STUB1 downregulates TOP2A through a dual mechanism of ubiquitination and FOXM1-mediated transcription repression, suppressing breast cancer growth and enhancing sensitivity to chemotherapy.","authors":"Baohui Yue, Qiaoling Xiang, Huimin Qiu, Mingxiang Huang, Mengxin Qi, Xianglan Yi, Sheng Zhou, Jing Xiong","doi":"10.1186/s11658-026-00902-2","DOIUrl":"10.1186/s11658-026-00902-2","url":null,"abstract":"<p><p>BACKGROUND: DNA topoisomerase IIɑ (TOP2A) is crucial for maintaining genomic stability and is an important target for genotoxic chemotherapeutic drugs. STIP1 homology and U-box-containing protein 1 (STUB1) is a U-box containing E3 ubiquitin ligase that participates in the degradation of specific oncogenic proteins. This research examined the potential regulatory function of STUB1 in relation to TOP2A, and explored its functional implications. METHODS: To identify interactions between STUB1 and TOP2A, coimmunoprecipitation, Glutathione S-transferases (GST) pull-down, and immunofluorescence assays were performed. Cycloheximide (CHX) pulse-chase assay, in vivo and in vitro ubiquitination, quantitative RT-PCR, chromatin immunoprecipitation (CHIP), and luciferase assays were performed to determine how STUB1 interacts with TOP2A. In addition, TOP2A catalytic activity, colony formation, WST-1, and flow cytometry assays were performed and a xenograft model was further developed to explore whether STUB1 could downregulate the catalytic activity of TOP2A, reduce the growth of breast cancer, and increase its sensitivity to doxorubicin. Moreover, immunohistochemical staining was conducted to assess STUB1 and TOP2A expression levels, as well as their predictive roles in the efficacy of neoadjuvant chemotherapy in individuals diagnosed with breast cancer. RESULTS: STUB1 enhanced TOP2A translocation to the cytoplasm, downregulating its expression through increased ubiquitination and degradation. Forkhead box M1 (FOXM1), another substrate of STUB1, served as a transcription factor for TOP2A, playing a role in STUB1-mediated downregulation of TOP2A at the transcriptional level. STUB1 inhibited TOP2A’s activity, reduced cancer cell proliferation, increased doxorubicin-induced apoptosis, and promoted cell cycle arrest. In a breast cancer xenograft model, STUB1 suppressed tumor growth and improved doxorubicin sensitivity. A positive correlation between FOXM1 and TOP2A expression was found in patients with breast cancer undergoing EC-T chemotherapy, both negatively correlated with STUB1, whose higher expression levels were linked to increased pathologic complete response (pCR) rates. STUB1 was evaluated as an independent predictor of pCR through univariate and multivariate analyses. CONCLUSIONS: This study proposes a novel function of STUB1 in the downregulation of TOP2A, which directly enhances sensitivity to chemotherapy. </p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479666","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":"NFAT1⁺ microglia promote antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1 axis to improve ischemic stroke outcomes.","authors":"Yaochuan Zhang, Xu Cao, Yifu Song, Xiaodi Han, Guofeng Tian, Dongxia Tao, Ana Hou, Sheng Han","doi":"10.1186/s11658-026-00906-y","DOIUrl":"10.1186/s11658-026-00906-y","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation and angiogenesis are central to post-stroke repair. However, the cellular and molecular mechanisms regulating these events remain incompletely understood. The nuclear factor of activated T cells-1 (NFAT1) is implicated in inflammation and vascular remodeling, yet its role in ischemic stroke is unclear.</p><p><strong>Methods: </strong>We established Nfat1-deficient (Nfat1^-/-) and Nfat1^+/+ stroke mice to investigate the role of NFAT1 in post-stroke inflammation and repair. Neurological outcomes, infarct volume, neuronal injury, synaptic protein expression, neuroinflammation, angiogenesis, and cerebral blood flow were assessed by behavioral test, magnetic resonance imaging (MRI), Nissl staining, western blotting, ELISA, immunofluorescence, and laser speckle imaging, respectively. ChIP, dual-luciferase, and mechanistic assays identified NFAT1 downstream targets and signaling pathways. Conditioned medium experiments examined the impact of Nfat1^+/+ primary microglia on endothelial cell behavior. NFAT1-overexpressing microglia were transplanted to assess therapeutic efficacy in vivo.</p><p><strong>Results: </strong>Nfat1^-/- stroke mice showed worsened neurological function, increased neuronal damage, and reduced expression of antiinflammatory and proangiogenic factors (interleukin (IL)-10, tumor growth factor (TGF)-β, VEGFA, and FGF2). NFAT1 deficiency impaired microglial polarization (CD163⁺ and CD206⁺), angiogenesis, and blood perfusion. NFAT1 upregulated HAS3 and LYVE1, promoting HA-LYVE1 autocrine/paracrine signaling and activation of the Wnt/β-catenin pathway, which facilitated antiinflammatory polarization. Conditioned medium experiments confirmed that Nfat1^+/+ microglia enhanced endothelial cell proliferation, migration, and tube formation. NFAT1-overexpressing microglia therapy enhanced antiinflammatory responses and angiogenesis, improved neurological recovery (e.g. Garcia score at day 35 increased by 0.87 points versus control), and reduced infarct size (corrected infarct area decreased by 27.29 units) in stroke mice.</p><p><strong>Conclusions: </strong>Microglial NFAT1 drives antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1-Wnt/β-catenin axis, ultimately improving stroke recovery. These findings reveal a previously unrecognized mechanism of neurovascular repair and highlight NFAT1⁺ microglia as a promising therapeutic target for ischemic stroke.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479648","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":"Dichotomous SMAD2/3 regulation and selective antihypertrophic activity of heparin during in vitro chondrogenesis of mesenchymal stromal cells.","authors":"Sven Schmidt, Safak Chasan, Helen F Dietmar, Felicia A M Klampfleuthner, Eliane Hesse, Tilman Walker, Uwe Freudenberg, Wiltrud Richter, Solvig Diederichs","doi":"10.1186/s11658-026-00899-8","DOIUrl":"10.1186/s11658-026-00899-8","url":null,"abstract":"<p><strong>Background: </strong>Endochondral instead of chondral differentiation hinders mesenchymal stromal cell (MSC) application for clinical cartilage regeneration. We previously showed that heparin-polyethylene glycol (PEG) hydrogels loaded with transforming growth factor TGF-β instructed stable chondral MSC development in vivo. Here, we assessed this approach in vitro, utilizing heparin-PEG hydrogels or the pellet culture system with soluble heparin supplementation of chondrogenic medium.</p><p><strong>Methods: </strong>Human MSCs were cultured in heparin-PEG hydrogels (22.4 mg/mL crosslinked heparin, 120 ng TGF-β1) or as pellet cultures treated with soluble heparin (0, 10, 100, 700 μg/mL) in TGF-β1-containing (10 ng/mL) chondrogenic medium. Chondral and endochondral signaling (1-3 h, 4 weeks) and cartilage matrix formation (4 weeks) were analyzed using western blot, histology, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and enzyme activity.</p><p><strong>Results: </strong>Unlike in vivo, human MSCs differentiated in heparin-PEG hydrogels into type X collagen and alkaline phosphatase-positive hypertrophic chondrocytes in vitro. Interestingly, treating MSC pellets with soluble heparin (10-700 µg/mL) revealed reduced TGF-β-SMAD3 but not SMAD2 activation at unaffected type II collagen and proteoglycan/DNA levels. We propose that the stimulation of the insulin-AKT pathway by heparin aided in maintaining SMAD2 activation, which apparently plays a more prominent role than SMAD3 for MSC chondrogenesis. Heparin treatment inhibited the pro-hypertrophic WNT/β-catenin pathway in vitro but insufficiently silenced TGF-β-SMAD1/5/9 activation and unfortunately reduced antihypertrophic prostaglandin PGE2 levels. Ultimately, treatment with 10 µg/mL heparin reduced the upregulation of several hypertrophy markers (MEF2C, IHH, IBSP messenger RNAs [mRNAs], alkaline phosphatase activity) below control levels, but type X collagen remained unresponsive. Thus, soluble heparin treatment was similarly selective and effective as previous antihypertrophic interventions (PTHrP pulses, WNT inhibition), while offering technical simplicity, reduced cost, and solvent-free formulation.</p><p><strong>Conclusions: </strong>Taken together, heparin-TGF-β showed a novel dichotomous SMAD2/3 inhibition at maintained chondrogenic differentiation and context-dependent lineage-instructive properties-permitting endochondral commitment in vitro but chondral development in vivo. Thus, environmental contributions are mandatory to allow heparin-PEG-guided chondral versus endochondral lineage commitment of MSCs in vivo, potentially involving SMAD1/5/9 suppressors and PGE2 sources.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13064404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472438","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":"Endothelial Ffar4 protects against diabetic kidney disease by potentiating endogenous retinoic acid metabolism.","authors":"Jiayu Li, Siyuan Cui, Wei Wang, Tingting Zhang, Zhe Wang, Xianlong Ye, Yong Q Chen, Shenglong Zhu","doi":"10.1186/s11658-026-00883-2","DOIUrl":"10.1186/s11658-026-00883-2","url":null,"abstract":"<p><p>BACKGROUND: Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide, and a complex interaction of genetic and environmental dietary factors may be involved. Free fatty acid receptor 4 (Ffar4) may serve as a link between the genetic and dietary aspects of DKD progression; however, its role in DKD remains unclear. METHODS: Ffar4-mediated DKD protection was evaluated using comprehensive genetic models. In addition, the effects of Ffar4 on glomerular inflammation and endothelial injury in mice were evaluated in vivo and in vitro, and the regulation of the Aldh1a1 gene by Ffar4 to maintain endogenous retinoic acid (RA) metabolic balance and related signaling pathways in the glomeruli was investigated. RESULTS: We found that Ffar4 expression was decreased in diabetes and was associated with renal complications. Conventional and endothelial-specific Ffar4 knockout exacerbated DKD, whereas endothelial-specific Ffar4 overexpression improved renal function. Mechanistically, Ffar4 regulated endogenous RA metabolism in the glomeruli through the Atf4–Aldh1a1 pathway. RA supplementation partially reversed DKD progression in endothelial-specific Ffar4 knockout mice. CONCLUSIONS: Taken together, these findings revealed a novel role of Ffar4 in potentiating endogenous RA production and delaying the progression of DKD-related multi-dysfunction. </p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13107635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147455373","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}