Cell Biology and Toxicology最新文献

{"title":"Improving hepatic metabolic function with 3D iPSC-derived human hepatocytes.","authors":"Victoria Pozo Garcia, Mostafa Kiamehr, Robin Versteegden, Elisabeth Naderlinger, Paul Jennings, Catherine Verfaillie, J Chris Vos, Sofia Moco","doi":"10.1007/s10565-026-10203-1","DOIUrl":"10.1007/s10565-026-10203-1","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (iPSCs) have the potential to significantly advance drug discovery and clinical applications, particularly in personalized medicine. Synthetic biocompatible materials improve the reproducibility and efficiency of in vitro protocols and enable three-dimensional (3D) cell culture. 3D spheroids and organoids are known to promote hepatic maturation and improve overall liver function. In this study, 3D hepatocyte-like cells (3D HLCs) were differentiated from human iPSCs using a synthetic polypeptide hydrogel scaffold. Their metabolic capacity, including drug biotransformation and mitochondrial function, was assessed using LC-MS semi-targeted metabolomics, providing functional characterization beyond marker expression levels. Compared with conventional monolayer (2D) cultures, 3D HLCs displayed a more mature hepatic phenotype. They acquired xenobiotic metabolism capacity earlier in differentiation, at day 30 rather than day 40 in 2D HLCs. In addition, 3D HLCs showed increased CYP3A4 activity (> 20-fold) and CYP2D6 activity (2-11-fold), as well as enhanced mitochondrial function, including higher β-oxidation, relative to 2D HLCs. The cytotoxic effects of eight drug-induced liver injury (DILI) compounds-amiodarone, azathioprine, cyclosporine A, diclofenac, nefazodone, omeprazole, rosiglitazone, and troglitazone-were also evaluated in 2D and 3D HLCs and compared with 2D primary human hepatocytes (2D PHHs). Drug exposure caused lower cell viability in 3D than in 2D HLCs, more closely resembling the response observed in 2D PHHs. Overall, this study demonstrates the applicability of 3D HLCs for metabolism and toxicology studies, with potential value for personalized drug testing and disease modeling.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein phosphatase 2A/Hedgehog pathway governs efferocytosis of pulmonary macrophages and participates in nanoplastics-induced mouse lung injury.","authors":"Jiaxin Zhang, Yuwei Zhang, Lixian Wen, Ziyan Li, Yulu Cai, Mengting Wan, Wenxue Li, Xiaonian Zhu, Yaqin Pang, Daochuan Li, Shen Chen, Ping Guo, Qing Wang, Wen Chen, Liping Chen","doi":"10.1007/s10565-026-10207-x","DOIUrl":"10.1007/s10565-026-10207-x","url":null,"abstract":"<p><p>Although inhalation of nanoplastics (NPs) is widely recognized as a trigger of pulmonary injury, the mechanisms underlying lung damage induced by orally ingested NPs remain largely uncharacterized. Computational toxicology profiling predicted the involvement of efferocytosis in nanoplastic toxicity. Protein phosphatase 2A (PP2A) is an important regulator of macrophage function, and PP2A Aα deficiency impaired efferocytosis. To delineate the contribution of efferocytosis to nanoplastics-induced pulmonary toxicity, myeloid-specific PP2A Aα-deficient (HO) mice model (Ppp2r1a gene deletion) and matched wild-type (WT) littermates were administrated with polystyrene nanoplastics (PS-NPs) by gavage at dose of 10 mg/kg·bw for 4 successive weeks. PS-NPs treatment led to sex-dependent lung inflammation, oxidative damage, and apoptosis in WT mice, which were further aggravated in HO mice. Proteomics analysis revealed impaired efferocytosis in HO mice was associated with perturbations in protein kinase A, ERK/MAPK, Hedgehog signaling pathway etc. In vitro studies confirmed that PP2A Aα deficiency dysregulated Hedgehog signaling, thereby suppressing macrophage efferocytosis and exacerbating pulmonary injury following PS-NPs exposure. Notably, we identified biochanin A as a compound capable of attenuating PS-NPs-induced pulmonary inflammation by enhancing efferocytosis. Together, these findings uncover a novel PP2A-Hedgehog-efferocytosis axis in NPs-induced pulmonary injury and highlight biochanin A as a potential intervention candidate for particulate pollutants-associated respiratory diseases.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple sevoflurane exposures in early development lead to long-term vascular abnormalities in the hippocampus.","authors":"Yu Matsumoto, Kazue Hashimoto-Torii, Masaaki Torii","doi":"10.1007/s10565-026-10206-y","DOIUrl":"10.1007/s10565-026-10206-y","url":null,"abstract":"<p><p>Children who undergo multiple exposures to anesthesia for surgeries and procedures are at increased risk of developing neurocognitive impairments. Growing evidence suggests that anesthesia-induced neurotoxicity and acute damage to neural cells underlie these impairments. However, the mechanisms underlying the long-term adverse effects of early anesthetic exposure remain largely unknown. Here, we show that repeated early-life exposures to sevoflurane, a commonly used anesthetic in clinical practice, lead to long-term impairments in hippocampal vascular architecture, characterized by reduced vascular area and branching complexity, associated with alterations in postsynaptic density composition. Mechanistically, sevoflurane exposure was associated with evidence of impaired endothelial cell integrity and elevated circulating levels of the pro-inflammatory cytokine TNF-α. In vitro, physiologically relevant concentrations of TNF-α potentiated sevoflurane-induced endothelial cell injury, indicating that inflammatory signaling may exacerbate endothelial vulnerability. Together, these findings identify microvascular regression as a long-term consequence of early anesthetic exposure and suggest that preservation of endothelial integrity may represent a therapeutic strategy to mitigate or prevent anesthesia-associated neurodevelopmental risk.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The HDAC1 inhibitor attenuates renal ischemia-reperfusion injury via dual epigenetic modulation of p53 and macrophage NF-κB pathways.","authors":"Qian-Qian Zhang, Chen-Zhen Yu, Fei-Hong Yu, Yong-Bo Wang, Song Chen, Zhong-Hua Klaus Chen, Wei-Jie Zhang, Sheng Chang","doi":"10.1007/s10565-026-10202-2","DOIUrl":"10.1007/s10565-026-10202-2","url":null,"abstract":"<p><strong>Background: </strong>The renal regenerative capacity hinges on tubular epithelial cell (TEC) plasticity, while Macrophage activation and their crosstalk with tubular cells further drive ischemia-reperfusion injury (IRI) progression, where epigenetic regulation critically directs cellular fate. Based on the established association between HDAC dysregulation-specifically HDAC1-and renal injury, we investigated the therapeutic strategies and and epigenetic regulatory mechanisms underlying mechanisms of the selective HDAC1 inhibitor FK228 in renal IRI.</p><p><strong>Methods: </strong>This study employed IRI animal models, along with in vitro culture systems of TECs and bone marrow-derived macrophages (BMDMs). A range of immunological and molecular biology techniques was used to assess TEC apoptosis and repair, as well as macrophage migration and polarization, with key molecular changes and their interactions visualized, too.</p><p><strong>Results: </strong>Our findings demonstrate that FK228 confers renoprotection in renal IRI through HDAC1-dependent modulation of p53 activity, coordinating the regulation of apoptotic pathways (P53-Caspase-3) and proliferative responses in tubular epithelium while attenuating oxidative stress and modulating macrophage crosstalk. And beyond that, FK228 delays IRI progression and fibrosis by inhibiting the HDAC1-HIF-1α-NF-κB signaling axis, thereby suppressing morphological transformation and limiting macrophage proliferation and differentiation. Confocal microscopy revealed that FK228 redistributes phosphorylated NF-κB p65 and HIF-1α to the cytoplasm while reducing their nuclear co-localization.</p><p><strong>Conclusion: </strong>In conclusion, This study demonstrates that FK228 protects TECs from IRI by modulating the p53-Caspase-3/Bcl-2 pathway to inhibit apoptosis. Additionally, FK228 targets the HDAC1-HIF-1α-NF-κB axis to suppress pathological macrophage polarization, thereby delaying renal fibrosis and ameliorating both acute injury and its chronic progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma.","authors":"Lei Wang, Hongyan Zhang, Yue Hu, Xingqiang Li, Jing Liu, Ying Liang","doi":"10.1007/s10565-026-10192-1","DOIUrl":"10.1007/s10565-026-10192-1","url":null,"abstract":"<p><p>Ubiquitination, a key post-translational modification, is responsible for regulating protein stability, activity, subcellular localization, and interactions via the ubiquitin-proteasome system (UPS). The UPS plays a role in non-lysosomal protein degradation, involved in the coordinated action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). The review elaborates on the functions of key E3 ligases of MDM2, β-TrCP, and SCF complexes, which modulate cell cycle progression, apoptosis, metabolic reprogramming, and drug resistance in hepatocellular carcinoma (HCC). For instance, MDM2 promotes HCC development by degrading the tumor suppressor p53, while β-TrCP influences the Wnt/β-catenin signaling axis by changing β-catenin levels. Deubiquitinating enzymes (DUBs), including the USP family and CYLD, also play significant roles in HCC by stabilizing or destabilizing critical proteins involved in oncogenesis. The clinical potential of ubiquitination-related molecules as biomarkers for predicting HCC prognosis and as therapeutic targets is also discussed. This review comprehensively examines the role of ubiquitination modification in HCC and its clinical relevance. Future research directions include the exploration of novel ubiquitination modifications, their interactions with other post-translational modifications, and the development of precision medicine strategies based on multi-omics technologies to improve HCC treatment outcomes.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13323521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Troxerutin suppresses the stemness of hepatocellular carcinoma via the Syk/FOXO3 feedback loop.","authors":"Shan Liu, Yuan Lin, Huan Xia, Hanhan Li, Yan Dou, Jiamin Luo, Tiantian Yang, Qi Zeng, Wei Guo, Hanrui Chen","doi":"10.1007/s10565-026-10194-z","DOIUrl":"10.1007/s10565-026-10194-z","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide due to its high rates of recurrence and metastasis. This underscores the urgent need to develop innovative drugs and treatment strategies to improve patient outcomes. This study examined the molecular pathways underlying troxerutin's therapeutic potential in HCC, providing information that could aid in the development of novel therapeutic strategies. Cell proliferation and apoptosis were assessed using CCK-8, EdU assays, and flow cytometry. Protein expression and mRNA alterations were analyzed by Western blotting and PCR, respectively. Cell migration and invasion were evaluated using Transwell assays, while tumor cell stemness was examined through sphere formation assays. Troxerutin's functional role was studied using in vivo models. Proteomic profiling of troxerutin-treated cells was performed using iTRAQ combined with LC-MS/MS to identify differentially expressed proteins (DEPs). Furthermore, luciferase reporter and ChIP assays were conducted to elucidate the underlying regulatory mechanisms. These findings demonstrate that troxerutin markedly inhibits HCC malignancy and stemness in both in vitro and in vivo models. Bioinformatics analysis indicated that the FOXO and SYK signaling pathways were predominantly enriched among the differentially expressed proteins. Mechanistically, we show that Syk dephosphorylation activates FOXO3 and facilitates its translocation into the nucleus. Moreover, we confirm that FOXO3 directly associates with the Syk promoter, thereby initiating its transcription. The present study reveals that troxerutin attenuates HCC progression by targeting the FOXO3/Syk feedback loop, inhibiting the stem-like properties of HCC cells.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of gut and oral microbiota in methamphetamine-induced multi-organ toxicity.","authors":"Jiebin Rong, Jingshen Zhuang, Jialong Xu, Xia Yue, Xuebing Chen","doi":"10.1007/s10565-026-10182-3","DOIUrl":"10.1007/s10565-026-10182-3","url":null,"abstract":"<p><p>Methamphetamine (METH) is an illicit stimulant that is in widespread use worldwide. Repeated intake of METH can lead to addiction and multiple-organ damage, which has become a globalized problem. However, the mechanism of METH toxicity remains unclear. The gut and oral microbiota and their metabolites have an impact on host behavior, metabolism, nutrition, and immune response. The available research find that METH not only disrupts the intestinal microbiota, but also alters the metabolites produced by the intestinal microbiota, such as reducing the levels of short-chain fatty acids (SCFAs), indole derivatives and inosine, and increasing the levels of trimethylamine N-oxide and lipopolysaccharide (LPS). The gut microbiota and their metabolites can participate in mediating METH-induced multi-organ toxicity via the intestinal immune interface and the gut-organ axis, thereby regulating processes such as oxidative stress, inflammatory responses, and mitochondrial damage. Concurrently, therapeutic approaches targeting the affected gut microbiota (including probiotic, microbiota transplantation, SCFAs, and indole derivatives) have also been demonstrated to effectively mitigate damage caused by METH abuse. The objective of this review is to establish a link between METH and the microbiota from the gut and oral cavity, based on the available evidence, to gain insight into the potential bidirectional roles of the gut and oral microbiota in METH addiction and METH-related multi-organ toxicity, and to develop future therapeutic strategies.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPSB3-mediated K48- and K63- linked ubiquitination and degradation of TUFM promote apoptosis induced by myocardial ischemia/reperfusion injury.","authors":"Yuyao Yin, Yaofeng Xie, Xiao Wang, Yuan Tan, Xiaodong Li, Yilong Pan","doi":"10.1007/s10565-026-10199-8","DOIUrl":"10.1007/s10565-026-10199-8","url":null,"abstract":"<p><p>Hypoxia, caused by various factors, significantly threatens human health by damaging the heart and cardiomyocytes. Revascularization strategies can sometimes precipitate adverse clinical outcomes due to myocardial ischemia/reperfusion (I/R) injury. The primary objective of this investigation was to explore the mechanism underlying myocardial I/R injury to identify novel alleviating strategies. CRISPR/Cas9 technology was used for high-throughput screening of hypoxia/reoxygenation (H/R)-tolerant genes; afterward, the genes were intersected with differentially expressed genes in the GSE61592 dataset. Subsequent validation identified SPRY domain-containing SOCS box protein 3 (SPSB3) as a critical gene that confers resistance to H/R injury. Increased apoptosis and worse heart function were observed in mouse and cardiomyocyte models of myocardial I/R injury. These pathological alterations coincided with a marked elevation in SPSB3 expression. Furthermore, SPSB3 inhibition substantially attenuated the myocardial I/R injury-induced increase in cardiomyocyte apoptosis, decrease in cardiac function, and mitochondrial dysfunction. To identify SPSB3 substrates, we combined the results from mass spectrometry, ubiquitin-modified proteomics, and the MitoCarta3.0 database (cardiac mitochondrial proteins), yielding six candidate molecules. Co-immunoprecipitation and western blot analyses indicated that SPSB3 may bind to Tu translation elongation factor, mitochondrial (TUFM). In SPSB3-knockdown cardiomyocytes, additional TUFM knockdown partially reversed the protective effect of SPSB3 knockdown alone. Additionally, MG132 and Cycloheximide treatment effectively inhibited TUFM degradation. Further amino acid site mutagenesis and other analyses revealed that SPSB3 inhibition prevents K48- and K63-linked ubiquitination at the K259 residue of TUFM and TUFM degradation, providing a promising therapeutic avenue for mitigating myocardial I/R injury.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13341827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subthalamic CaMKIIα-expressing neurons facilitate recovery from propofol anesthesia via the STN-ventral pallidum pathway.","authors":"Shangqin Bai, Yiqiu Chen, Yu Li, Xiao Liu, Yanyan Ba, Qingbin Chen, Xiangqing Song, Haisheng Zhang, Xiaochun Lai, Lin Xue, Pei Sun, He Zhu, Jingyu Xiao, Wen Li, Xuejun Wang","doi":"10.1007/s10565-026-10195-y","DOIUrl":"10.1007/s10565-026-10195-y","url":null,"abstract":"<p><p>Propofol is extensively used in clinical anesthesia, yet its mechanisms of action remain incompletely understood. CaMKIIα-expressing neurons in the subthalamic nucleus (STN) have been associated with arousal-related pain perception and impulse regulation, but their role in propofol anesthesia remains unclear. In this study, c-Fos immunohistochemistry, live calcium-signal recording by fiber photometry, electroencephalography (EEG), and electromyography (EMG) were employed to assess the activity of STN CaMKIIα-expressing neurons during propofol anesthesia. It was observed that the activity of STN CaMKIIα-expressing neurons was markedly reduced under propofol anesthesia. Both optogenetic and chemogenetic activation of this population promoted cortical arousal and shortened recovery time without affecting anesthetic induction. Through anterograde and retrograde tracing approaches, a direct projection from the STN to the ventral pallidum (VP) was identified. Optogenetic stimulation of STN CaMKIIα-expressing axon terminals within the VP modified EEG spectral power during maintenance and emergence and enhanced emergence from propofol anesthesia. Collectively, these findings indicate that STN CaMKIIα-expressing neurons play an important role in promoting behavioral emergence from propofol anesthesia, at least partially through the STN-VP circuit. This study provides circuit-level evidence that improves mechanistic insight into emergence from general anesthesia and identifies the STN-VP pathway as a potential target for modulating anesthetic recovery.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13287289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL14 modulates the autophagy-pyroptosis pathway in fibroblasts by modifying BECN1 through m⁶A methylation to promote wound healing in DFUs and SYD treatment.","authors":"Zhaowei Wang, Zongqiang Wei, Qinyao Yu, Linru Wang, Kai Liu, Hongjie Wang, Qiang Li","doi":"10.1007/s10565-026-10196-x","DOIUrl":"10.1007/s10565-026-10196-x","url":null,"abstract":"<p><strong>Background: </strong>Diabetic foot ulcers (DFUs) are prevalent complication in diabetes. METTL14 serves as a key regulator of both autophagy and pyroptosis, both essential for the healing of DFUs. Simiao Yong'an Decoction (SYD) has demonstrated potential in promoting skin wound healing. This study investigates how METTL14 functions as a main regulator in DFU wound healing during SYD treatment and explores the underlying mechanisms.</p><p><strong>Methods: </strong>Both qPCR and western blot assays were performed to determine METTL14 and BECN1 expression. DFU rat models and fibroblasts stimulated with high glucose (HG) were used to evaluate the role of METTL14 in autophagy, pyroptosis, pro-angiogenic ability, and wound healing through both loss- and gain-of-function assays. The association between METTL14 and BECN1 was examined via MeRIP and RNA stability assays. Futhermore, the therapeutic effects of SYD on DFUs were assessed.</p><p><strong>Results: </strong>Exposure to HG reduced METTL14 levels in fibroblasts, resulting in reduced cell viability and migration, lowered autophagy, and increased pyroptosis. Increasing METTL14 expression reversed these cellular impairments and enhanced angiogenesis driven by fibroblasts. Mechanistically, METTL14 stabilized BECN1 mRNA via m⁶A modification. In a rodent DFU model, overexpression of METTL14 accelerated wound healing, improved angiogenesis, and regulated autophagy and pyroptosis; these beneficial effects were partially reversed when BECN1 was knocked down. Furthermore, treatment with SYD increased METTL14 expression, promoted wound closure, angiogenesis, and autophagy, while reducing pyroptosis; these positive outcomes were significantly reduced when METTL14 was knocked down.</p><p><strong>Conclusions: </strong>METTL14-mediated m⁶A modification of BECN1 influences autophagy, pyroptosis, and angiogenesis to enhance wound healing in DFUs. METTL14 serves as a key regulator in SYD-mediated wound repair, offering a novel therapeutic strategy for treating DFUs.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}