Mi Liu, Jiacheng Hu, Jiayi Huang, Zhefeng Cai, Peng Zou, Jing Bu, Shanshan Yu, Yuxi Zhou, Xiaoqiong Jiang, Lianfang Gan, Shuhong Tian, Lei Dong, Fenzan Wu, Huiming Deng, Jian Xiao
Background Random skin flaps application is considerably limited by postoperative complications, particularly distal tissue ischemia and necrosis. Melatonin, a molecule with well-documented antioxidant and cytoprotective properties, has shown promise in protecting ischemic tissues. However, its specific role in regulating ferroptosis during ischemic flap injury, as well as its safety and efficacy in primate models (a key step for clinical translation), remains to be systematically validated. In this study, we aimed to promote angiogenesis within flap tissue through exogenous melatonin administration, and to inhibit ferroptosis to mitigate ischemia-reperfusion injury, presenting a novel strategy for enhancing flap survival rates. Methods A random skin flap was constructed in C57BL/6J mice. After melatonin treatment for seven days, the influence of melatonin on the levels of oxidative stress, iron accumulation, and mitochondrial morphology within the skin flap tissue were assessed. We used Transwell migration assays, tube formation assays, flow cytometry and immunofluorescence staining to determine the effects of melatonin in vitro. The ferroptosis inducer erastin was used in combination with melatonin to treat random skin flap mice and Tert-butyl hydroperoxide (TBHP) induced cellular models, And the pathway through which melatonin counteracts iron mutations was explored. Lastly, we conducted experiments using nonhuman primate (NHP) models and analyzed the protective effects of melatonin on ischemic flaps in macaques, highlighting its potential for clinical translation. Results Melatonin ameliorated the survival area of ischemic flaps in mice, enhanced angiogenesis, reduced mitochondrial damage, and also suppressed lipid peroxidation and iron ion accumulation. Melatonin attenuated TBPH-induced cell death, lipid peroxidation, and mitochondrial damage in vitro. Further mechanistic studies revealed that melatonin inhibited ferroptosis, accompanied by nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), and increases the expression of downstream gene (effector) heme oxygenase-1 (HO-1). More importantly, experiments in macaques demonstrated that melatonin could enhance flap viability and angiogenesis, and exhibited good safety profile. Conclusion Melatonin enhanced flap viability in mice and macaques by inhibiting ferroptosis, boosting angiogenesis, and attenuating oxidative stress injury.
{"title":"Melatonin promotes skin flap survival by inhibiting ferroptosis","authors":"Mi Liu, Jiacheng Hu, Jiayi Huang, Zhefeng Cai, Peng Zou, Jing Bu, Shanshan Yu, Yuxi Zhou, Xiaoqiong Jiang, Lianfang Gan, Shuhong Tian, Lei Dong, Fenzan Wu, Huiming Deng, Jian Xiao","doi":"10.1093/burnst/tkag012","DOIUrl":"https://doi.org/10.1093/burnst/tkag012","url":null,"abstract":"Background Random skin flaps application is considerably limited by postoperative complications, particularly distal tissue ischemia and necrosis. Melatonin, a molecule with well-documented antioxidant and cytoprotective properties, has shown promise in protecting ischemic tissues. However, its specific role in regulating ferroptosis during ischemic flap injury, as well as its safety and efficacy in primate models (a key step for clinical translation), remains to be systematically validated. In this study, we aimed to promote angiogenesis within flap tissue through exogenous melatonin administration, and to inhibit ferroptosis to mitigate ischemia-reperfusion injury, presenting a novel strategy for enhancing flap survival rates. Methods A random skin flap was constructed in C57BL/6J mice. After melatonin treatment for seven days, the influence of melatonin on the levels of oxidative stress, iron accumulation, and mitochondrial morphology within the skin flap tissue were assessed. We used Transwell migration assays, tube formation assays, flow cytometry and immunofluorescence staining to determine the effects of melatonin in vitro. The ferroptosis inducer erastin was used in combination with melatonin to treat random skin flap mice and Tert-butyl hydroperoxide (TBHP) induced cellular models, And the pathway through which melatonin counteracts iron mutations was explored. Lastly, we conducted experiments using nonhuman primate (NHP) models and analyzed the protective effects of melatonin on ischemic flaps in macaques, highlighting its potential for clinical translation. Results Melatonin ameliorated the survival area of ischemic flaps in mice, enhanced angiogenesis, reduced mitochondrial damage, and also suppressed lipid peroxidation and iron ion accumulation. Melatonin attenuated TBPH-induced cell death, lipid peroxidation, and mitochondrial damage in vitro. Further mechanistic studies revealed that melatonin inhibited ferroptosis, accompanied by nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), and increases the expression of downstream gene (effector) heme oxygenase-1 (HO-1). More importantly, experiments in macaques demonstrated that melatonin could enhance flap viability and angiogenesis, and exhibited good safety profile. Conclusion Melatonin enhanced flap viability in mice and macaques by inhibiting ferroptosis, boosting angiogenesis, and attenuating oxidative stress injury.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"41 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chengyao Han, Beibei Wu, Chunxiao Cui, Peiru Min, Xinxian Meng, Yuhao Sun, Ke Wen, Chuanliang Feng, Yixin Zhang, Xueqian Wang, Ke Li
The lymphatic system serves many more functions than simply in maintaining tissue fluid homeostasis, and its structural and functional changes indicate the occurrence of disease. Current clinical methods for the assessment of the lymphatic system, however, are severely limited because of their nontargeting ability, invasiveness, high cost, and radiation risk. Herein, we propose a simple and painless method for visualizing and quantifying the lymphatic system. This method is based on the noninvasive administration of a novel lymphatic tracer via dissolvable microneedles (MNs), followed by the application of a portable detection device for near-infrared (NIR) imaging. The tracer is prepared by incorporating the clinically approved NIR fluorescent dye methylene blue (ME) into nanomaterials (MPEG-PCL@ME). This novel tracer displays superior fluorescence properties, stability, biocompatibility, and targeting features in comparison with ME solution alone. Lymphography with MPEG-PCL@ME in vivo clearly revealed the lymphatic vessel morphology. Notably, compared with ME and ICG, MPEG-PCL@ME can easily identify the dominant lymphatic vessels and nodes in rats with higher imaging quality. Furthermore, a series of segmental contracting sections are detected with MPEG-PCL@ME, allowing straightforward identification of the lymphatic pump, which provides direct evidence for exquisitely evaluating lymphatic functions.
{"title":"A novel method for targeting lymphatic vessel imaging: methylene blue nanoparticle integrated with dissolvable microneedles","authors":"Chengyao Han, Beibei Wu, Chunxiao Cui, Peiru Min, Xinxian Meng, Yuhao Sun, Ke Wen, Chuanliang Feng, Yixin Zhang, Xueqian Wang, Ke Li","doi":"10.1093/burnst/tkaf067","DOIUrl":"https://doi.org/10.1093/burnst/tkaf067","url":null,"abstract":"The lymphatic system serves many more functions than simply in maintaining tissue fluid homeostasis, and its structural and functional changes indicate the occurrence of disease. Current clinical methods for the assessment of the lymphatic system, however, are severely limited because of their nontargeting ability, invasiveness, high cost, and radiation risk. Herein, we propose a simple and painless method for visualizing and quantifying the lymphatic system. This method is based on the noninvasive administration of a novel lymphatic tracer via dissolvable microneedles (MNs), followed by the application of a portable detection device for near-infrared (NIR) imaging. The tracer is prepared by incorporating the clinically approved NIR fluorescent dye methylene blue (ME) into nanomaterials (MPEG-PCL@ME). This novel tracer displays superior fluorescence properties, stability, biocompatibility, and targeting features in comparison with ME solution alone. Lymphography with MPEG-PCL@ME in vivo clearly revealed the lymphatic vessel morphology. Notably, compared with ME and ICG, MPEG-PCL@ME can easily identify the dominant lymphatic vessels and nodes in rats with higher imaging quality. Furthermore, a series of segmental contracting sections are detected with MPEG-PCL@ME, allowing straightforward identification of the lymphatic pump, which provides direct evidence for exquisitely evaluating lymphatic functions.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"38 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiuying Guo, Lele Liu, Junqi Yang, Yuhe Dai, Qianbo Zhang, Rifang Gu, Min Tan, Ming Tang, Xuqiang Nie
Wound healing is a highly coordinated biological process traditionally divided into three phases: Inflammatory, proliferative, and remodeling. Diabetes and acute trauma markedly disrupt these stages, resulting in delayed wound closure, persistent inflammation, and impaired tissue regeneration. This review focuses on three trauma-relevant contexts: (i) Skin wounds, including diabetic ulcers and burns; (ii) bone fracture healing; (iii) corneal epithelial and stromal injury. Robust in vivo evidence is synthesized to delineate the mechanistic roles of the four principal RNA modifications: N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N4-acetylcytidine. Additionally, the roles of RNA modification writers, erasers, and readers in regulating macrophage polarization, stem and progenitor cell fate, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling are examined. Evidence across different tissues and wound healing phases is integrated rather than presented descriptively. Methodological limitations are highlighted, and knowledge gaps are identified alongside testable hypotheses. Translational opportunities with direct relevance to burn and trauma management are emphasized. This review aims to integrate mechanistic and translational insights into a coherent framework for therapeutic intervention. By defining how RNA modifications intersect with distinct wound healing phases, concrete therapeutic entry points and delivery strategies relevant to burns and trauma are identified, including topical hydrogels, exosome-based therapies, and bone-targeted nanoparticles. Designs for pragmatic clinical trials and biomarker strategies that enable translation of preclinical findings to patients are also discussed.
{"title":"RNA Modifications: Molecular Orchestrators of Wound Healing","authors":"Xiuying Guo, Lele Liu, Junqi Yang, Yuhe Dai, Qianbo Zhang, Rifang Gu, Min Tan, Ming Tang, Xuqiang Nie","doi":"10.1093/burnst/tkag010","DOIUrl":"https://doi.org/10.1093/burnst/tkag010","url":null,"abstract":"Wound healing is a highly coordinated biological process traditionally divided into three phases: Inflammatory, proliferative, and remodeling. Diabetes and acute trauma markedly disrupt these stages, resulting in delayed wound closure, persistent inflammation, and impaired tissue regeneration. This review focuses on three trauma-relevant contexts: (i) Skin wounds, including diabetic ulcers and burns; (ii) bone fracture healing; (iii) corneal epithelial and stromal injury. Robust in vivo evidence is synthesized to delineate the mechanistic roles of the four principal RNA modifications: N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N4-acetylcytidine. Additionally, the roles of RNA modification writers, erasers, and readers in regulating macrophage polarization, stem and progenitor cell fate, angiogenesis, lymphangiogenesis, and extracellular matrix remodeling are examined. Evidence across different tissues and wound healing phases is integrated rather than presented descriptively. Methodological limitations are highlighted, and knowledge gaps are identified alongside testable hypotheses. Translational opportunities with direct relevance to burn and trauma management are emphasized. This review aims to integrate mechanistic and translational insights into a coherent framework for therapeutic intervention. By defining how RNA modifications intersect with distinct wound healing phases, concrete therapeutic entry points and delivery strategies relevant to burns and trauma are identified, including topical hydrogels, exosome-based therapies, and bone-targeted nanoparticles. Designs for pragmatic clinical trials and biomarker strategies that enable translation of preclinical findings to patients are also discussed.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"50 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Noxious lifestyle factors including spicy diets and hot baths may lead to scar formation and recurrence. These phenomena are related to the activation of the transient receptor potential vanilloid (TRPV1) cation channel. Our previous study revealed significant upregulation of TRPV1 expression in the dermis of hypertrophic scar (HS), while the exact underlying mechanism of TRPV1 activation in HS remains ill-defined. Methods Firstly, this study employs single-cell RNA sequencing technology to analyze the association between vascular endothelial cells and the development of HS. Complementarily, bioinformatics analysis combined with histological validation is utilized to investigate the relationship between TRPV1 channels and aberrant angiogenesis within HS formation. Furthermore, the correlation between TRPV1 activation and HS phenotypes is rigorously validated at the in vivo level. In parallel, in vitro experiments are conducted to elucidate the impact of TRPV1 channel activation on the biological behaviors and functions of vascular endothelial cells. Subsequently, key downstream signaling pathways of TRPV1 are screened, and their molecular mechanisms in regulating vascular endothelial cell-mediated angiogenesis are systematically verified. Finally, a comprehensive analysis is performed to establish the clinical relevance of the TRPV1/nuclear factor kappa-B (NF-κB)/interleukin-6 (IL-6) axis with vascularization severity and adverse prognostic outcomes in hypertrophic scarring. Results Single-cell RNA sequencing revealed significant cellular heterogeneity in vascular endothelial cells between normal skin (NS) and HS, indicating activated angiogenesis and substantial vascular endothelial cell alterations during HS development. Bulk RNA-seq and clinical analyses further confirmed this angiogenesis activation, demonstrating a close association with TRPV1 channel activation. In vivo studies established that capsaicin (CAP)-induced TRPV1 activation exacerbated HS progression through enhanced angiogenesis, whereas TRPV1 ablation or local inhibition markedly attenuated this effect. In vitro experiments demonstrated TRPV1 activation regulated angiogenesis by promoting pro-angiogenic phenotypes. Transcriptomic analysis and functional validation identified the IL-6/Signal Transducer and Activator of Transcription 3 (STAT3) pathway as a downstream NF-κB-dependent pro-angiogenic axis mediated by TRPV1 in HS vascular endothelial cells. Critically, dermal overexpression of the TRPV1/NF-κB/IL-6 axis in HS patients correlated strongly with both disease severity and recurrence. Conclusions Here, we show that the development of HS is strongly correlated with endothelial angiogenic activity. TRPV1 activation by CAP enhances proangiogenic processes including endothelial proliferation, migration and tubule formation, while reducing apoptosis through the TRPV1/ NF-κB/ IL-6 axis. In a rabbit ear HS model, stimulation of TRPV1 contributes to the formation of HS
背景：辛辣饮食和热水浴等有害的生活方式因素可能导致疤痕的形成和复发。这些现象与瞬时受体电位香草蛋白（TRPV1）阳离子通道的激活有关。我们之前的研究显示TRPV1在增生性瘢痕真皮（HS）中的表达显著上调，而TRPV1在HS中激活的确切潜在机制尚不清楚。方法本研究首先采用单细胞RNA测序技术分析血管内皮细胞与HS发生的关系。此外，利用生物信息学分析结合组织学验证来研究TRPV1通道与HS形成中异常血管生成的关系。此外，TRPV1激活与HS表型之间的相关性在体内水平上得到了严格的验证。同时进行体外实验，阐明TRPV1通道激活对血管内皮细胞生物学行为和功能的影响。随后，筛选TRPV1的关键下游信号通路，系统验证其调控血管内皮细胞介导的血管生成的分子机制。最后，综合分析TRPV1/核因子κ b (NF-κB)/白细胞介素-6 （IL-6）轴与肥厚性瘢痕血管化严重程度和不良预后的临床相关性。结果单细胞RNA测序结果显示，正常皮肤（NS）和HS之间血管内皮细胞存在明显的细胞异质性，表明HS发育过程中血管生成被激活，血管内皮细胞发生了实质性改变。大量RNA-seq和临床分析进一步证实了这种血管生成激活，表明与TRPV1通道激活密切相关。体内研究证实，辣椒素（CAP）诱导的TRPV1激活通过增强血管生成加剧了HS的进展，而TRPV1消融或局部抑制显著减弱了这一作用。体外实验表明，TRPV1激活通过促进促血管生成表型来调节血管生成。转录组学分析和功能验证表明，IL-6/信号转导和转录激活因子3 （STAT3）通路是HS血管内皮细胞中TRPV1介导的下游NF-κ b依赖性促血管生成轴。重要的是，HS患者皮肤中TRPV1/NF-κB/IL-6轴的过表达与疾病严重程度和复发密切相关。结论：HS的发生与内皮血管生成活性密切相关。CAP激活TRPV1可增强促血管生成过程，包括内皮细胞增殖、迁移和小管形成，同时通过TRPV1/ NF-κB/ IL-6轴减少细胞凋亡。在兔耳HS模型中，刺激TRPV1通过TRPV1/NF-κB/IL-6轴促进HS的形成，而药物消融TRPV1可显著逆转这些表型。这些发现揭示了潜在的分子机制，并为HS提供了潜在的治疗靶点。
{"title":"Modulating Hypertrophic Scar Formation by Targeting Endothelial TRPV1/NF-κB/IL-6 Axis to Regulate Angiogenesis","authors":"Hao Ma, Liuhanghang Cheng, Ruoyu Ling, Jingyi Chen, Shunuo Zhang, Shujing Lin, Liang Ding, Chengliang Deng, Yixin Zhang, Peiru Min","doi":"10.1093/burnst/tkag009","DOIUrl":"https://doi.org/10.1093/burnst/tkag009","url":null,"abstract":"Background Noxious lifestyle factors including spicy diets and hot baths may lead to scar formation and recurrence. These phenomena are related to the activation of the transient receptor potential vanilloid (TRPV1) cation channel. Our previous study revealed significant upregulation of TRPV1 expression in the dermis of hypertrophic scar (HS), while the exact underlying mechanism of TRPV1 activation in HS remains ill-defined. Methods Firstly, this study employs single-cell RNA sequencing technology to analyze the association between vascular endothelial cells and the development of HS. Complementarily, bioinformatics analysis combined with histological validation is utilized to investigate the relationship between TRPV1 channels and aberrant angiogenesis within HS formation. Furthermore, the correlation between TRPV1 activation and HS phenotypes is rigorously validated at the in vivo level. In parallel, in vitro experiments are conducted to elucidate the impact of TRPV1 channel activation on the biological behaviors and functions of vascular endothelial cells. Subsequently, key downstream signaling pathways of TRPV1 are screened, and their molecular mechanisms in regulating vascular endothelial cell-mediated angiogenesis are systematically verified. Finally, a comprehensive analysis is performed to establish the clinical relevance of the TRPV1/nuclear factor kappa-B (NF-κB)/interleukin-6 (IL-6) axis with vascularization severity and adverse prognostic outcomes in hypertrophic scarring. Results Single-cell RNA sequencing revealed significant cellular heterogeneity in vascular endothelial cells between normal skin (NS) and HS, indicating activated angiogenesis and substantial vascular endothelial cell alterations during HS development. Bulk RNA-seq and clinical analyses further confirmed this angiogenesis activation, demonstrating a close association with TRPV1 channel activation. In vivo studies established that capsaicin (CAP)-induced TRPV1 activation exacerbated HS progression through enhanced angiogenesis, whereas TRPV1 ablation or local inhibition markedly attenuated this effect. In vitro experiments demonstrated TRPV1 activation regulated angiogenesis by promoting pro-angiogenic phenotypes. Transcriptomic analysis and functional validation identified the IL-6/Signal Transducer and Activator of Transcription 3 (STAT3) pathway as a downstream NF-κB-dependent pro-angiogenic axis mediated by TRPV1 in HS vascular endothelial cells. Critically, dermal overexpression of the TRPV1/NF-κB/IL-6 axis in HS patients correlated strongly with both disease severity and recurrence. Conclusions Here, we show that the development of HS is strongly correlated with endothelial angiogenic activity. TRPV1 activation by CAP enhances proangiogenic processes including endothelial proliferation, migration and tubule formation, while reducing apoptosis through the TRPV1/ NF-κB/ IL-6 axis. In a rabbit ear HS model, stimulation of TRPV1 contributes to the formation of HS ","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"19 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rong Zhang, Tianhao Li, Fengzhou Du, Jiuzuo Huang, Nanze Yu, Xiao Long
As cellular energy metabolic hubs, mitochondria undergo dynamic fusion–fission cycles and autophagy that enable rapid adaptation to cellular energy demands and stress conditions. In addition to their role in energy metabolism, mitochondria are integral to cellular homeostasis and regulate cell cycle progression, differentiation, and apoptosis pathways. In recent years, the importance of mitochondrial function in skin health and disease has garnered increasing attention. Mitochondrial dysfunction has been implicated in a spectrum of skin disorders, including skin ageing, psoriasis, vitiligo, keloids, scleroderma, and skin cancer. The pathogenesis of these conditions is closely linked to mitochondrial DNA (mtDNA) damage, excessive reactive oxygen species (ROS) production, and alterations in mitochondrial metabolic pathways. In terms of therapeutic strategies, this review summarizes a range of mitochondrion-targeted interventions. These treatments include the activation of the PGC-1α pathway to increase mitochondrial ATP synthesis, the use of antioxidants to mitigate mitochondrial ROS production, and the application of bioactive compounds and drugs to protect mitochondria or promote mtDNA repair. These approaches not only contribute to improved skin health but also provide novel insights for the treatment of skin diseases. Additionally, mitochondrial transplantation technology has shown considerable promise in skin regeneration and wound healing and is emerging as a new frontier for skin tissue repair.
{"title":"Mitochondrial Dynamics in Skin Health and Disease: Energy, Ageing, and Therapeutic Perspectives","authors":"Rong Zhang, Tianhao Li, Fengzhou Du, Jiuzuo Huang, Nanze Yu, Xiao Long","doi":"10.1093/burnst/tkag008","DOIUrl":"https://doi.org/10.1093/burnst/tkag008","url":null,"abstract":"As cellular energy metabolic hubs, mitochondria undergo dynamic fusion–fission cycles and autophagy that enable rapid adaptation to cellular energy demands and stress conditions. In addition to their role in energy metabolism, mitochondria are integral to cellular homeostasis and regulate cell cycle progression, differentiation, and apoptosis pathways. In recent years, the importance of mitochondrial function in skin health and disease has garnered increasing attention. Mitochondrial dysfunction has been implicated in a spectrum of skin disorders, including skin ageing, psoriasis, vitiligo, keloids, scleroderma, and skin cancer. The pathogenesis of these conditions is closely linked to mitochondrial DNA (mtDNA) damage, excessive reactive oxygen species (ROS) production, and alterations in mitochondrial metabolic pathways. In terms of therapeutic strategies, this review summarizes a range of mitochondrion-targeted interventions. These treatments include the activation of the PGC-1α pathway to increase mitochondrial ATP synthesis, the use of antioxidants to mitigate mitochondrial ROS production, and the application of bioactive compounds and drugs to protect mitochondria or promote mtDNA repair. These approaches not only contribute to improved skin health but also provide novel insights for the treatment of skin diseases. Additionally, mitochondrial transplantation technology has shown considerable promise in skin regeneration and wound healing and is emerging as a new frontier for skin tissue repair.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"14 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhichao Ruan, Yi Zheng, Guoyong Jiang, Jing Chen, Jiahe Guo, Chengqi Yan, Dong Liu, Shuoyuan Liu, Yufeng Wang, Pengjuan Nie, Diandian Li, Zijie Chen, Jia Tian, Zhenbing Chen, Xiaofan Yang
Background Diabetic wounds remain difficult to treat due to persistent oxidative stress, chronic inflammation, and vascular dysfunction. These factors reinforce each other, forming a vicious cycle that leads to delayed healing, poor angiogenesis, and high amputation risk. Existing therapies often fail because they are unable to address these challenges simultaneously. Therefore, this study aimed to develop a hybrid extracellular vesicle system that targets these multiple barriers concurrently to promote diabetic wound healing. Methods A biohybrid nanovesicle system (DFO@HEVs) was built by fusing endothelial cell-derived extracellular vesicles with neutrophil-derived nanovesicles (forming hybrid extracellular vesicles, HEVs), which were loaded with deferoxamine (DFO). The vesicles were tested for their physicochemical properties, drug loading, and safety. Therapeutic effects were studied in vitro using HG/PA-stimulated endothelial cells and macrophages and in vivo in diabetic mouse wounds. The analyses included microscopy, flow cytometry, histology, transcriptomics, and database-based single-cell RNA sequencing. Results DFO@HEVs showed dual targeting: homing to endothelial cells via CXCR4 and to inflamed sites via β2 integrin. They enhanced endothelial uptake, promoted angiogenesis through PI3K/AKT/HIF-1α and VEGF signaling pathways, and reduced oxidative stress and ferroptosis by activating Nrf2 and upregulating antioxidant genes. They also shifted macrophages toward an anti-inflammatory M2 phenotype, boosted efferocytosis, and suppressed NF-κB/NLRP3-driven inflammation. In diabetic mice, treatment with DFO@HEVs accelerated wound closure, re-epithelialization, collagen deposition, and new vessel formation, while lowering neutrophil infiltration, ROS levels, ferroptosis, and pro-inflammatory cytokines, creating a healing-supportive environment. Conclusions DFO@HEVs provided a hybrid nanovesicle system for combined membrane and drug delivery. By promoting angiogenesis, limiting ferroptosis, and resolving inflammation, they disrupted the cycle that prevented diabetic wound repair. This approach shows a strong potential as a new treatment for chronic wounds.
{"title":"Hybrid Nanovesicles Promote Diabetic Wound Healing via Dual-Targeted Multimodal Therapy","authors":"Zhichao Ruan, Yi Zheng, Guoyong Jiang, Jing Chen, Jiahe Guo, Chengqi Yan, Dong Liu, Shuoyuan Liu, Yufeng Wang, Pengjuan Nie, Diandian Li, Zijie Chen, Jia Tian, Zhenbing Chen, Xiaofan Yang","doi":"10.1093/burnst/tkag004","DOIUrl":"https://doi.org/10.1093/burnst/tkag004","url":null,"abstract":"Background Diabetic wounds remain difficult to treat due to persistent oxidative stress, chronic inflammation, and vascular dysfunction. These factors reinforce each other, forming a vicious cycle that leads to delayed healing, poor angiogenesis, and high amputation risk. Existing therapies often fail because they are unable to address these challenges simultaneously. Therefore, this study aimed to develop a hybrid extracellular vesicle system that targets these multiple barriers concurrently to promote diabetic wound healing. Methods A biohybrid nanovesicle system (DFO@HEVs) was built by fusing endothelial cell-derived extracellular vesicles with neutrophil-derived nanovesicles (forming hybrid extracellular vesicles, HEVs), which were loaded with deferoxamine (DFO). The vesicles were tested for their physicochemical properties, drug loading, and safety. Therapeutic effects were studied in vitro using HG/PA-stimulated endothelial cells and macrophages and in vivo in diabetic mouse wounds. The analyses included microscopy, flow cytometry, histology, transcriptomics, and database-based single-cell RNA sequencing. Results DFO@HEVs showed dual targeting: homing to endothelial cells via CXCR4 and to inflamed sites via β2 integrin. They enhanced endothelial uptake, promoted angiogenesis through PI3K/AKT/HIF-1α and VEGF signaling pathways, and reduced oxidative stress and ferroptosis by activating Nrf2 and upregulating antioxidant genes. They also shifted macrophages toward an anti-inflammatory M2 phenotype, boosted efferocytosis, and suppressed NF-κB/NLRP3-driven inflammation. In diabetic mice, treatment with DFO@HEVs accelerated wound closure, re-epithelialization, collagen deposition, and new vessel formation, while lowering neutrophil infiltration, ROS levels, ferroptosis, and pro-inflammatory cytokines, creating a healing-supportive environment. Conclusions DFO@HEVs provided a hybrid nanovesicle system for combined membrane and drug delivery. By promoting angiogenesis, limiting ferroptosis, and resolving inflammation, they disrupted the cycle that prevented diabetic wound repair. This approach shows a strong potential as a new treatment for chronic wounds.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"120 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Forecasting the global burden of peripheral artery disease: implications for wound healing and healthcare systems.","authors":"Seungkuk Ahn,Min He","doi":"10.1093/burnst/tkag003","DOIUrl":"https://doi.org/10.1093/burnst/tkag003","url":null,"abstract":"","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"30 1","pages":"tkag003"},"PeriodicalIF":5.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoxiang Wang, Sitong Zhou, Yixun Zhang, Xuewei Zhang, Shuilan Wu, Yan Huang, Julin Xie, Kun Xiong, Ronghua Yang
Background PANoptosis is a comprehensive form of cell death regulation that involves the interplay of pyroptosis, apoptosis, and necrosis. As a key regulator of PANoptosis, TAK1 plays a crucial role in multiple cell death pathways. However, its specific mechanism in the process of diabetic wound (DW) healing remains unclear. This study aimed to explore the role of TAK1 in regulating PANoptosis and its impact on DW healing. Methods We used immunofluorescence, TUNEL staining, and EthD-III staining to analyse the relationship between TAK1 activity and PANoptosis. RNA sequencing was used to investigate the regulatory role of TAK1 and the NF-κB pathway under high-glucose conditions. Additionally, molecular docking and co-IP experiments were performed to verify the interaction between TAK1 and p65. Finally, a mouse model was used to study the effects of TAK1 knockdown on wound healing. Results Our findings revealed that PANoptosis is significantly present in DW, with markedly upregulated TAK1 expression under high-glucose conditions. The inhibition of TAK1 expression significantly reduced cell death and promoted cell proliferation and migration. Mechanistically, TAK1 interacts with p65 through the NF-κB pathway, activating downstream signals that exacerbate cell damage in a high-glucose environment. TAK1 knockdown significantly suppressed PANoptosis, promoted microvascular and collagen formation, reduced inflammation, and further accelerated wound healing. Conclusion TAK1 regulates PANoptosis by activating the NF-κB signalling pathway, thereby playing a crucial role in DW healing. Inhibiting TAK1 may represent a potential strategy to improve wound healing, with significant potential for clinical application.
{"title":"TAK1 activates PANoptosis through the NF-κB signalling pathway to delay diabetic wound healing","authors":"Xiaoxiang Wang, Sitong Zhou, Yixun Zhang, Xuewei Zhang, Shuilan Wu, Yan Huang, Julin Xie, Kun Xiong, Ronghua Yang","doi":"10.1093/burnst/tkag001","DOIUrl":"https://doi.org/10.1093/burnst/tkag001","url":null,"abstract":"Background PANoptosis is a comprehensive form of cell death regulation that involves the interplay of pyroptosis, apoptosis, and necrosis. As a key regulator of PANoptosis, TAK1 plays a crucial role in multiple cell death pathways. However, its specific mechanism in the process of diabetic wound (DW) healing remains unclear. This study aimed to explore the role of TAK1 in regulating PANoptosis and its impact on DW healing. Methods We used immunofluorescence, TUNEL staining, and EthD-III staining to analyse the relationship between TAK1 activity and PANoptosis. RNA sequencing was used to investigate the regulatory role of TAK1 and the NF-κB pathway under high-glucose conditions. Additionally, molecular docking and co-IP experiments were performed to verify the interaction between TAK1 and p65. Finally, a mouse model was used to study the effects of TAK1 knockdown on wound healing. Results Our findings revealed that PANoptosis is significantly present in DW, with markedly upregulated TAK1 expression under high-glucose conditions. The inhibition of TAK1 expression significantly reduced cell death and promoted cell proliferation and migration. Mechanistically, TAK1 interacts with p65 through the NF-κB pathway, activating downstream signals that exacerbate cell damage in a high-glucose environment. TAK1 knockdown significantly suppressed PANoptosis, promoted microvascular and collagen formation, reduced inflammation, and further accelerated wound healing. Conclusion TAK1 regulates PANoptosis by activating the NF-κB signalling pathway, thereby playing a crucial role in DW healing. Inhibiting TAK1 may represent a potential strategy to improve wound healing, with significant potential for clinical application.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"22 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background The spatiotemporal regulation of inflammatory dynamics is critical for successful wound healing. However, the precise mechanistic role of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in orchestrating these processes remains incompletely characterized. This study aimed to delineate the specific mechanisms by which NLRP3 governs cellular and molecular events during wound healing. Methods Multi-omics sequencing data were utilized to profile NLRP3 inflammasome activation dynamics in murine and human acute wound models. Nlrp3-/- mice were generated using CRISPR-Cas9 technology. In vitro and in vivo functional assays were performed to assess NLRP3-dependent regulation of macrophage and fibroblast recruitment, polarization, and phenotype modulation. Results NLRP3 is predominantly expressed in macrophages and neutrophils during the inflammatory phase of wound healing. Global deletion of Nlrp3 reduces IL-1β, the main downstream effector, attenuates CCL/CXCL chemokine signaling, decreases both inflammatory and reparative cell infiltration, and disrupts the phenotypic switching of macrophages and fibroblasts, collectively delaying wound closure. However, the resulting low-inflammatory microenviroment in Nlrp3-/- mice may upregulate Wnt and Notch signaling early in the repair phase, curbing fibrosis and promoting appendage regeneration. Partial IL-1β blockade in WT mice recapitulates the NLRP3-null phenotype, whereas IL-1β reconstitution in knockout mice accelerates healing but increases fibrosis. Moreover, the NLRP3 protein also modulates fibroblast phenotype independently of inflammasome activation. Conclusion NLRP3 exerts dual-phase regulatory roles in wound healing: (1) During inflammation, it drives chemokine-mediated macrophage/fibroblast recruitment and M1 polarization while suppressing fibroblast repair via IL-1β signaling; (2) Later, NLRP3 deficiency enhances Wnt/Notch signaling, promoting structural restoration despite transiently delayed healing. Moreover, Fibroblasts with high NLRP3 expression engage an inflammasome-independent NLRP3/ROS axis that augments activtion of TGF-β/Smad signaling. These findings position NLRP3 as a potential therapeutic target for modulating phase-specific inflammatory and regenerative responses.
{"title":"Spatiotemporal regulation of Acute Wound Healing by the NLRP3 Inflammasome: Dual Roles in Macrophage-Fibroblast chemotaxis and phenotype during wound repair","authors":"Dongzhen Zhu, JianJun Li, Bingyang Yu, Nanbo Liu, Xu Guo, Yanlin Su, Yuzhen Wang, Yuyan Huang, Liting Liang, Linhao Hou, Chao Zhang, Qinghua Liu, Mengde Zhang, Wei Song, Yi Kong, Jinpeng Du, Zhao Li, Yue Kong, Feng Tian, Xiangye Yin, Ping Zhu, Xiaobing Fu, Sha Huang","doi":"10.1093/burnst/tkag002","DOIUrl":"https://doi.org/10.1093/burnst/tkag002","url":null,"abstract":"Background The spatiotemporal regulation of inflammatory dynamics is critical for successful wound healing. However, the precise mechanistic role of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in orchestrating these processes remains incompletely characterized. This study aimed to delineate the specific mechanisms by which NLRP3 governs cellular and molecular events during wound healing. Methods Multi-omics sequencing data were utilized to profile NLRP3 inflammasome activation dynamics in murine and human acute wound models. Nlrp3-/- mice were generated using CRISPR-Cas9 technology. In vitro and in vivo functional assays were performed to assess NLRP3-dependent regulation of macrophage and fibroblast recruitment, polarization, and phenotype modulation. Results NLRP3 is predominantly expressed in macrophages and neutrophils during the inflammatory phase of wound healing. Global deletion of Nlrp3 reduces IL-1β, the main downstream effector, attenuates CCL/CXCL chemokine signaling, decreases both inflammatory and reparative cell infiltration, and disrupts the phenotypic switching of macrophages and fibroblasts, collectively delaying wound closure. However, the resulting low-inflammatory microenviroment in Nlrp3-/- mice may upregulate Wnt and Notch signaling early in the repair phase, curbing fibrosis and promoting appendage regeneration. Partial IL-1β blockade in WT mice recapitulates the NLRP3-null phenotype, whereas IL-1β reconstitution in knockout mice accelerates healing but increases fibrosis. Moreover, the NLRP3 protein also modulates fibroblast phenotype independently of inflammasome activation. Conclusion NLRP3 exerts dual-phase regulatory roles in wound healing: (1) During inflammation, it drives chemokine-mediated macrophage/fibroblast recruitment and M1 polarization while suppressing fibroblast repair via IL-1β signaling; (2) Later, NLRP3 deficiency enhances Wnt/Notch signaling, promoting structural restoration despite transiently delayed healing. Moreover, Fibroblasts with high NLRP3 expression engage an inflammasome-independent NLRP3/ROS axis that augments activtion of TGF-β/Smad signaling. These findings position NLRP3 as a potential therapeutic target for modulating phase-specific inflammatory and regenerative responses.","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"2 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-22eCollection Date: 2026-01-01DOI: 10.1093/burnst/tkaf078
Hao Feng, Xiao Yu, Gonghao Zhang, Zhengchao Yuan, Abdullah M Al-Enizi, Cheng Xue Qin, Mohamed El-Newehy, Xiumei Mo
Tendon-bone interface injuries, such as rotator cuff tears and anterior cruciate ligament ruptures, remain challenging due to the enthesis's complex structure and poor healing capacity. Conventional repair often fails to restore the fibrocartilaginous transition, causing mismatched integration and high retear rates. Biomaterial-based scaffolds provide biomechanical support and bioactive regulation, showing great promise for regeneration. Recent advances span natural polymers, synthetic polymers, bioceramics, and composites, with designs evolving from monophasic to multiphasic, gradient-based, and functionalized scaffolds. Emerging strategies emphasize immunomodulation, bio-signal delivery, and physical responsiveness, establishing a structure-signal-function paradigm to guide multi-tissue integration. However, translation faces major barriers, including inadequate animal models, manufacturing and scalability challenges, long-term safety concerns, and regulatory complexity, as well as the need to balance personalization with cost. Future directions point to intelligent biomaterials, AI-driven design, and integrated translational frameworks to bridge preclinical research and clinical application. Overall, advanced scaffold engineering offers transformative potential for functional tendon-bone regeneration, but successful translation will depend on close collaboration among biology, materials science, engineering, and medicine.
{"title":"Advanced engineering strategies for biomaterial scaffolds application in tendon-bone interface regeneration.","authors":"Hao Feng, Xiao Yu, Gonghao Zhang, Zhengchao Yuan, Abdullah M Al-Enizi, Cheng Xue Qin, Mohamed El-Newehy, Xiumei Mo","doi":"10.1093/burnst/tkaf078","DOIUrl":"10.1093/burnst/tkaf078","url":null,"abstract":"<p><p>Tendon-bone interface injuries, such as rotator cuff tears and anterior cruciate ligament ruptures, remain challenging due to the enthesis's complex structure and poor healing capacity. Conventional repair often fails to restore the fibrocartilaginous transition, causing mismatched integration and high retear rates. Biomaterial-based scaffolds provide biomechanical support and bioactive regulation, showing great promise for regeneration. Recent advances span natural polymers, synthetic polymers, bioceramics, and composites, with designs evolving from monophasic to multiphasic, gradient-based, and functionalized scaffolds. Emerging strategies emphasize immunomodulation, bio-signal delivery, and physical responsiveness, establishing a structure-signal-function paradigm to guide multi-tissue integration. However, translation faces major barriers, including inadequate animal models, manufacturing and scalability challenges, long-term safety concerns, and regulatory complexity, as well as the need to balance personalization with cost. Future directions point to intelligent biomaterials, AI-driven design, and integrated translational frameworks to bridge preclinical research and clinical application. Overall, advanced scaffold engineering offers transformative potential for functional tendon-bone regeneration, but successful translation will depend on close collaboration among biology, materials science, engineering, and medicine.</p>","PeriodicalId":9553,"journal":{"name":"Burns & Trauma","volume":"14 ","pages":"tkaf078"},"PeriodicalIF":9.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12821377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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