The FASEB Journal最新文献

{"title":"Lycium barbarum Polysaccharide Ameliorates Hindlimb Unloading-Induced Bone Loss by Targeting Noggin","authors":"Chuanxin Sun,&nbsp;Yuke He,&nbsp;Xia Chen,&nbsp;Kan Ding,&nbsp;Chang Chen","doi":"10.1096/fj.202403082R","DOIUrl":"https://doi.org/10.1096/fj.202403082R","url":null,"abstract":"<div>\u0000 \u0000 <p>Disuse bone loss is a common metabolic bone disease with limited effective, safe treatments. <i>Lycium barbarum</i> (<i>L. barbarum</i>), a traditional Chinese medicine and popular health food, has been historically noted in Ben Cao Gang Mu (Compendium of Materia Medica) for its bone-strengthening properties. However, the effects of <i>L. barbarum</i> on disuse bone loss and the underlying mechanisms remain unclear. This study used a hindlimb-unloading mouse model and a simulated microgravity model of MC3T3-E1 cells in a rotary cell culture system to investigate the role of <i>L. barbarum</i> water extract (LBE) and polysaccharide (LBP). LBE and LBP significantly enhanced bone mass and strength in hindlimb-unloaded mice. Further analysis identified a polysaccharide component, LBPP, as the active ingredient mediating these effects. LBPP enhanced osteoblast differentiation and ossification under normal conditions and promoted osteoblast activity under simulated microgravity. Mechanistic studies revealed that LBPP directly binds to noggin, a potent inhibitor of BMPs, facilitating phosphorylation of downstream Smads to stimulate bone formation. These findings demonstrate the potential of <i>L. barbarum</i> as a functional food for preventing disuse bone loss and provide a theoretical basis for its therapeutic applications.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric Oxide Scavenging Alleviates Scar Pruritus by Inhibiting S-Nitrosylation of Transient Receptor Potential Channels and Limiting Calcium Influx","authors":"Jiaqiang Wang,&nbsp;Bo Yuan,&nbsp;Shan Zhong,&nbsp;Hsin-Ying Liu,&nbsp;Jie Zhang,&nbsp;Xuelian Chen,&nbsp;Yunsheng Chen,&nbsp;Yan Liu","doi":"10.1096/fj.202403020R","DOIUrl":"https://doi.org/10.1096/fj.202403020R","url":null,"abstract":"<div>\u0000 \u0000 <p>Scar pruritus, a common and debilitating symptom in burn patients, significantly impacts quality of life. This study investigates the therapeutic potential of nitric oxide (NO) scavenging in alleviating scar pruritus by targeting the S-nitrosylation (SNO) of transient receptor potential (TRP) channels, which play a crucial role in pruritus sensation and transmission. We hypothesized that NO-induced SNO of TRP channels mediates scar pruritus and explored the effects of NO scavengers on pruritus-related features in scar tissue. We used hypertrophic scar (HS) and normal skin (NS) tissues from patients, HaCaT keratinocyte cell lines for in vitro studies, and a murine model for in vivo studies. NO scavengers, a combination of hemoglobin (HB) and N(omega)-nitro-L-arginine methyl ester (L-NM), were applied to assess their effects on NO, SNO, TRP channels, and pruritogen expression. RNA sequencing and proteomics were conducted to analyze differential gene and protein expression, respectively. NO levels, SNO, and calcium influx were measured using fluorescence probes, immunohistochemistry, and calcium imaging techniques. Scar tissues exhibited higher levels of pruritogens, NO, and SNO compared to normal skin, with increased expression of TRPV1, TRPV3, TRPV4, and TRPA1. NO scavenging reduced scratch behavior in mouse models of scar pruritus, decreased NO and SNO levels, and downregulated the expression of TRP channels. In vitro, NO scavengers inhibited SNO of TRPV1 and limited intracellular calcium influx in HaCaT cells stimulated with substance P (SP). Additionally, NO scavenging reduced the secretion of pruritus mediators such as thymic stromal lymphopoietin (TSLP), nerve growth factor (NGF), and interleukin-31 (IL-31). NO scavenging effectively alleviates scar pruritus by inhibiting the SNO of TRP channels, particularly TRPV1, and consequently limiting the influx of intracellular calcium ions. This study provides a novel therapeutic approach for scar pruritus and highlights the potential of NO scavengers in modulating itch sensation pathways.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt Activation in Mature Dermal Adipocytes Leads to Lipodystrophy and Skin Fibrosis via ATGL-Dependent Lipolysis","authors":"Qiannan Ma,&nbsp;Ella X. Segal,&nbsp;Miles A. Montegut,&nbsp;Suneeti R. Madhavan,&nbsp;Anna R. Jussila,&nbsp;Claire Reynolds,&nbsp;Rachel H. Wyetzner,&nbsp;Megan Gregory,&nbsp;Elif Ertugral,&nbsp;Chandrasekhar Kothapalli,&nbsp;Radhika P. Atit","doi":"10.1096/fj.202501380R","DOIUrl":"https://doi.org/10.1096/fj.202501380R","url":null,"abstract":"<p>Accumulation of extracellular matrix (ECM) and dermal adipocyte lipodystrophy occurs during skin fibrosis, which compromises the skin's flexibility and function. Sustained Wnt activation in dermal progenitor cells leads to fibrotic ECM thickening in the dermis and lipodystrophy of dermal white adipose tissue (DWAT). Mouse genetic models with lineage tracing demonstrate that Wnt activation in mature dermal adipocytes is sufficient to induce adipocyte lipodystrophy and fibrotic ECM remodeling in the skin. Upon withdrawal of adipocyte-restricted Wnt activation, lipodystrophy and fibrosis are reversed. Mechanistically, Wnt activation stimulates the Adipose Triglyceride Lipase (ATGL)-mediated lipolysis pathway, and lipolysis is an early event in the skin of Systemic Sclerosis patients. <i>Atgl</i> in dermal adipocytes is functionally required for Wnt-induced lipodystrophy in the DWAT and fibrotic remodeling. Collectively, this study demonstrates that Wnt activation in dermal adipocytes promotes lipolysis, suggesting a therapeutic avenue for the treatment of lipodystrophy and skin fibrosis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501380R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative and Apoptotic Effects of Mono/Combined Treatment of Abemaciclib and Regulation of Neuroblastoma-Related miRNAs","authors":"Burcu Çerçi Alkaç,&nbsp;Mustafa Soyöz,&nbsp;Tülay Kılıçaslan Ayna,&nbsp;Melek Pehlivan,&nbsp;İbrahim Pirim","doi":"10.1096/fj.202501315","DOIUrl":"https://doi.org/10.1096/fj.202501315","url":null,"abstract":"<div>\u0000 \u0000 <p>Neuroblastoma (NB), a common pediatric cancer, is often associated with poor prognosis due to resistance to conventional therapies. Abemaciclib, a selective inhibitor of CDK4/6, is known for its ability to block cell cycle progression and induce cell death in various cancer types. In this study, we explore its potential therapeutic impact on NB by assessing its effects on cell proliferation, apoptosis, and the regulation of microRNAs (miRNAs) that are related to NB progression. Antiproliferative effect of abemaciclib, doxorubicin, cisplatin, and temozolomide (TMZ) were detected by MTT method. Combinations of abemaciclib–doxorubicin, abemaciclib–cisplatin, and abemaciclib–TMZ were also investigated by applying IC50 doses of the drugs for 24 h. ELISA and flow cytometry were performed for apoptosis detection, and for cell cycle analysis, flow cytometry was used. The expression levels of eight apoptosis, threee tumor suppressors, two oncogenes, and nine cell cycle-related genes were analyzed by quantitative PCR. Moreover, the expression levels of five NB-related miRNAs were determined. IC50 doses of abemaciclib, doxorubicin, cisplatin, and TMZ were found to be 4.757, 1.958, 34.21, and 240.7 uM in the 24 h, respectively. The combination of the drugs increased apoptosis and decreased cell migration and colony formation rates. The highest expression level difference was observed in PUMA when control and dose groups were compared. Increased expression levels of hsa-mir-18a-5p and hsa-miR-124-3p were detected in all drug-treated groups compared to the control group. Our results highlight the potential of abemaciclib as a promising treatment strategy for NB, particularly when used in combination with other therapies to overcome resistance and improve clinical outcomes.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol Within Phosphatidylcholine Liposomes Attenuates the Expression of Cytokines","authors":"David M. Cauvi,&nbsp;Dennis Hawisher,&nbsp;Julia Derunes,&nbsp;Ikenna Aniegbuna,&nbsp;Antonio De Maio","doi":"10.1096/fj.202501458R","DOIUrl":"https://doi.org/10.1096/fj.202501458R","url":null,"abstract":"<p>Lipid nanoparticles (LNPs) have gained increased interest for their use as carriers of therapeutic drugs and vaccines. These particles can encapsulate high concentrations of chemical drugs and nucleic acids within their lumen, providing protection from the activity of lytic agents. The central components of LNPs are phospholipids that, due to their amphiphilic nature, spontaneously assemble into vesicular structures. The major phospholipid used for LNPs is phosphatidylcholine (PC), which is often supplemented with cholesterol and polyethylene glycol. Phospholipids within LNPs have been considered inert components. However, we have shown that liposomes made of palmitoyl oleoyl phosphatidylcholine (POPC) or palmitoyl oleoyl phosphatidylserine (POPS) induce a massive alteration of gene expression within macrophages (Mϕ), particularly genes involved in the inflammatory response. These observations suggest that phospholipids could play an independent biological role in modulating cellular responses. Since cholesterol plays a crucial role in cellular functions and is a regular component of LNPs, we investigated the effect of the sterol on the inflammatory response induced by POPC liposomes. We reported herewith that the presence of free cholesterol within liposomes reduces the inflammatory response induced by phospholipids. This effect was not recapitulated by esterified or water-soluble cholesterol and was not dependent on the acidification of late endosomes/lysosomes. Finally, the reduction in cytokine expression by the sterol was due to a decrease in the activation of NF-kB. Thus, the incorporation of cholesterol into LNPs suppresses the inflammatory response induced by the particles.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501458R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin and Kaempferol Mitigate Endotoxin-Induced Skeletal Muscle Wasting by Inhibiting KLF15 Expression and Restoring the Antioxidant System","authors":"Samanwita Mandal,&nbsp;Akash Mitra,&nbsp;Bipasha Bose,&nbsp;Sudheer Shenoy P","doi":"10.1096/fj.202501184R","DOIUrl":"https://doi.org/10.1096/fj.202501184R","url":null,"abstract":"<div>\u0000 \u0000 <p>The loss of muscle mass or muscle atrophy is a significant health concern associated with aging, diabetes, cardiovascular diseases, environmental toxicity, and inflammation, and it is becoming a significant issue requiring effective therapeutic strategies. Sepsis is caused by bacterial infection leading to inflammation and has a plethora of consequences, one of which is loss of muscle mass commonly observed for intensive care unit patients with a high morbidity rate. Flavonoids are well-known natural compounds for restoring muscle wasting. Our study investigates the efficacy of two flavonoids, quercetin and kaempferol, in mitigating lipopolysaccharide (LPS)-induced muscle atrophy. LPS treatment was followed by increased ROS production, upregulated inflammation (NF-Kβ, TLR4, MyD88, IL-6), and disruption of mitochondrial homeostasis in C2C12 myoblasts. The KLF15 knockdown cellular model also revealed a negligible effect of LPS in C2C12. Furthermore, the antioxidant properties of quercetin and kaempferol, individually and in combination, were evidenced to attenuate LPS-induced cellular oxidative stress and promote myogenesis by downregulating inflammatory regulators and atrophy-related genes triggered by LPS. Hence, this study illuminates the status of quercetin's and kaempferol's cytoprotective effect, individually and in combination, on muscle cells affected by sepsis-induced atrophy.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Two MPTP Doses on Mouse Behaviors and Pathologies","authors":"Yue Qi,&nbsp;Ziwei Zhang,&nbsp;Jinhua Xue,&nbsp;Suhua Yao,&nbsp;Xiaying Lu,&nbsp;Xiaolu Tang","doi":"10.1096/fj.202500467RR","DOIUrl":"https://doi.org/10.1096/fj.202500467RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson's disease (PD), a prevalent neurodegenerative disorder, is characterized by the selective and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, the presence of Lewy bodies (LBs) within neurons, and gliosis. The mouse model induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most commonly utilized animal models for PD; however, its ability to accurately replicate the full spectrum of motor and non-motor symptoms remains contentious. In this study, we employed novel MPTP administration regimens (160 and 240 mg/kg) to examine the behavioral phenotype and pathological alterations induced by MPTP injury, utilizing a combination of behavioral, molecular, and morphological methodologies. Our findings indicate that MPTP-induced subacute PD mice exhibited a significant loss of dopaminergic neurons in the ventral midbrain, accompanied by diffuse astrogliosis and activated microglia. Nonetheless, these mice did not display other prominent movement disorders or mood abnormalities, aside from the gait disturbances associated with the administered MPTP dose. Consequently, we propose that the MPTP-induced subacute PD mouse model utilized in this study represents an early preclinical stage analogous to that observed in human PD patients.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-Wide CRISPR-Cas9 Knockout Screening Identifies Genes Modulating Cisplatin-Induced Cytotoxicity in Renal Proximal Tubule Epithelial Cells","authors":"Sixu Wang,&nbsp;Jiaqi Zheng,&nbsp;Xiaofei Zhang,&nbsp;Meishan Zhao,&nbsp;Jun Li,&nbsp;Ming Su,&nbsp;Wei Qiu","doi":"10.1096/fj.202402401RR","DOIUrl":"https://doi.org/10.1096/fj.202402401RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Cisplatin is widely used as a first-line chemotherapy drug for various cancers. However, cisplatin-induced nephrotoxicity (CIN) greatly restricts its application. Renal proximal tubular epithelial cells (RPTECs) can be extensively damaged during CIN. However, it still lacks an ideal method to prevent CIN, because the mechanism and therapeutic targets of CIN remain largely unclear. In the present study, we used a genome-scale CRISPR-Cas9 knock-out method to functionally screen key genes of cisplatin-induced RPTEC injury. We found 815 genes significantly enriched (<i>p</i> &lt; 0.05) from positive selection screening strategy, which may synergistically enhance cisplatin cytotoxicity in RPTECs. Importantly, we identified ERAP2 as a novel molecule associated with CIN. We found that the expression of ERAP2 in RPTECs was significantly up-regulated by cisplatin. Data from CCK-8 assay and flow cytometry showed that inhibition of ERAP2 alleviated cisplatin-induced RPTEC injury. Furthermore, RNA-seq and qPCR results revealed that three necroptosis-associated genes, <i>PLA2G4C</i>, <i>HIST1H2AC</i>, and <i>HIST1H2AM</i>, were downregulated following ERAP2 inhibition, suggesting that ERAP2 may be a novel therapeutic target of CIN through the modulation of necroptosis pathway.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Invasive Ultrasound Treatment Enhances the Release of Skeletal Muscle-Derived Extracellular Vesicles in Mice","authors":"Atomu Yamaguchi,&nbsp;Xiaoqi Ma,&nbsp;Mikiko Uemura,&nbsp;Kento Tanida,&nbsp;Nozomi Nishimura,&nbsp;Jiaqi Tan,&nbsp;Gojiro Nakagami,&nbsp;Hiromi Sanada,&nbsp;Dongming Su,&nbsp;Kristopher Sarosiek,&nbsp;Hidemi Fujino,&nbsp;Noriaki Maeshige","doi":"10.1096/fj.202501797R","DOIUrl":"https://doi.org/10.1096/fj.202501797R","url":null,"abstract":"<div>\u0000 \u0000 <p>Skeletal muscle, the largest secretory organ, regulates distant organs through the secretion of various factors. Among these are extracellular vesicles (EVs), which play a significant role in mediating communication between muscle and other tissues and hold therapeutic potential due to their target specificity and anti-inflammatory properties. Enhancing the release of EVs from skeletal muscle into the circulation is crucial for eliciting their diverse effects, including anti-inflammatory actions; however, effective strategies to increase the levels of muscle-derived EVs in the bloodstream have not yet been developed. While exercise is the most studied method to increase blood EV levels, its efficacy in enhancing skeletal muscle-derived EVs remains unclear. This study reveals that a brief, 5-min ultrasound (US) treatment of skeletal muscle robustly elevates circulating levels of muscle-derived EVs, introducing a novel, non-invasive stategy to modulate EV release. US-induced EVs showed altered miRNA profiles enriched with anti-inflammatory miRNAs that target pathways involved in inflammatory responses. Additionally, transient upregulation of reactive oxygen species and activation of the endoplasmic reticulum stress pathway were observed in US-treated muscle, suggesting a mechanism for enhanced EV release. Our findings establish US as the first non-invasive and rapid method to selectively enhance skeletal muscle-derived EV release into the circulation, highlighting its potential for therapeutic applications through its anti-inflammatory effect.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Surgical Periodontal Therapy and Metformin Improve Bone Loss in Obese Mice With Periodontitis by Modulating the Gut Microbiota","authors":"Rixin Chen,&nbsp;Wei Wei,&nbsp;Lili Li,&nbsp;Miaomiao Zhang,&nbsp;Nannan Wang,&nbsp;Ruiyang Ge,&nbsp;Yue Shen,&nbsp;Wen Zhang,&nbsp;Daiyv Lu,&nbsp;Wenzheng Liao,&nbsp;Yanfen Li,&nbsp;Fuhua Yan","doi":"10.1096/fj.202501689R","DOIUrl":"https://doi.org/10.1096/fj.202501689R","url":null,"abstract":"<p>Periodontitis and obesity are chronic inflammatory diseases associated with osteoporosis. Controlling inflammation is crucial for managing periodontitis in individuals with obesity. Metformin has shown potent anti-inflammatory effects under inflammatory conditions. However, the effects of adjunctive systemic administration of metformin alongside non-surgical periodontal therapy (NSPT) on periodontal and systemic bone health in obesity remain unknown. In this study, a high-fat diet (HFD)-induced obese murine model was created with periodontitis through ligation. Periodontal treatment consisted of standard mechanical debridement via NSPT, with or without metformin treatment through oral gavage. Outcomes were evaluated based on changes in periodontal status, systemic bone resorption and inflammation, as well as the gut microbiota community and metabolism. Our results indicated that periodontitis significantly increased osteoclastic activity and resulted in alveolar and femoral bone loss in HFD-fed mice. Compared to NSPT alone, NSPT and metformin significantly improved periodontitis, reduced systemic inflammation, and alleviated femoral bone absorption in HFD-fed mice. Mechanistically, periodontitis promoted gut microbiota dysbiosis and disrupted microbial linoleic acid metabolism. NSPT and metformin normalized the gut microbiota, enhanced the growth of species with anti-inflammatory properties, including <i>Faecalibacterium prausnitzii</i>, <i>Akkermansia muciniphila</i>, <i>Lactobacillus reuteri</i>, and <i>Butyricicoccus pullicaecorum</i>, and restored the balance of linoleic acid metabolism in the gut and serum. This research presents novel evidence that metformin may serve as a promising adjunct to enhance the response of obese subjects to NSPT by regulating the gut microbiota and linoleic acid metabolism, indicating that the gut microbiota could be a potential therapeutic target for multidisciplinary intervention in periodontitis and obesity.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 13","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501689R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}