Inflammation最新文献

{"title":"Pharmacological Activation of GPR68 Attenuates Ferroptosis in Spinal Cord Ischemia/Reperfusion Injury Through PI3K/Akt-Mediated Nrf2 Antioxidant Pathway.","authors":"Ruitong Yang, Jintao Ye, Pengbo Wang, Tao Liu, Bin Cheng, Fengtao Li","doi":"10.1007/s10753-025-02326-0","DOIUrl":"https://doi.org/10.1007/s10753-025-02326-0","url":null,"abstract":"<p><p>Spinal cord ischemia-reperfusion injury (SCIRI) is a devastating condition with limited therapeutic options. This study unveils a novel role of G protein-coupled receptor 68 (GPR68), a pH-sensing G protein-coupled receptor (GPCR), in mitigating ferroptosis-a lipid peroxidation-driven cell death-through the Phosphoinositide 3-Kinase/ Protein Kinase B/ Nuclear Factor Erythroid 2-Related Factor 2 (PI3K/Akt/Nrf2) antioxidant axis. Using in vitro (Oxygen-Glucose Deprivation/Reperfusion (OGD/R)-treated Pheochromocytoma Cell Line 12 (PC12) cells ) and in vivo (rat spinal cord ischemia-reperfusion (I/R) ) models, we demonstrate that GPR68 downregulation exacerbates ferroptosis, evidenced by elevated Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), Malondialdehyde (MDA), and Oxidized Glutathione/ Total Glutathione (GSSG/T-GSH) levels, alongside reduced Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4). Pharmacological activation of GPR68 with MS48107 or the clinically approved benzodiazepine Lorazepam robustly reversed ferroptosis by enhancing Akt phosphorylation and Nrf2 nuclear translocation. Mechanistically, GPR68 siRNA or PI3K/Akt inhibition abolished these protective effects. Crucially, Lorazepam rescued neuronal viability and suppressed ferroptosis in spinal I/R rats, effects fully negated by the GPR68 antagonist Ogremorphin (OGM). Our findings establish GPR68 as a key ferroptosis regulator and propose repurposing Lorazepam as a therapeutic strategy for SCIRI.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SAA1 Promotes Ulcerative Colitis and Activating Colonic TLR4/NF-κB/NLRP3 Signaling Pathway.","authors":"Peixuan Zhu, Yujie Wu, Yateng Sun, Yonghuang Yan, Yanmin Wang, Yuling Yu, Jiusi Yang, Yuhan Wang, Zishuo Guo, Siqi Wang, Cai Zhang, Zeqi Su","doi":"10.1007/s10753-025-02299-0","DOIUrl":"https://doi.org/10.1007/s10753-025-02299-0","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a chronic inflammatory disease of the colorectal characterized by dysregulation of cytokine production resulting from abnormal innate and adaptive immune responses, which promote inflammation. Serum amyloid A (SAA) proteins are key components of the acute inflammatory response and have been found to be positively associated with UC disease activity in clinical studies. In this study, we employed a well-established DSS-induced UC model and conducted non-targeted proteomic detection to identify significantly differentially expressed proteins and related biological processes. Among these proteins, SAA1 was found to be significantly upregulated, showing functional enrichment in acute inflammatory pathways. Further investigation at both animal and cellular levels revealed that increased expression of SAA1 protein further enhanced the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-γ, IL-6, IL-9, IL-17A, IL-17F and IL-22 while promoting the formation of an inflammatory microenvironment in the colon. Importantly, inhibition of SAA1 effectively alleviated pathological manifestations and tissue damage in UC by down-regulating cytokine expression. Mechanistically, our findings confirmed that SAA1 activates the TLR4/NF-kB signaling pathway and promotes NLRP3 inflammasome activation along with secretion of pro-inflammatory cytokines including TNF-a, IFN-γ, and IL-6. This ultimately leads to colonic microenvironment formation and progression of UC. Overall, our results highlight the critical involvement of SAA1 in UC progression as well as its potential utility as an inflammatory marker or therapeutic target.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AR Deficiency Protects Against Sepsis-Induced Acute Lung Injury by Inhibiting Macrophage M1 Polarization and Inflammatory Cytokine Secretion.","authors":"Xiaowan Wang, Di Yin, Jiayan Sun, Linna Zhang, Yuheng Ye, Qiang Guo","doi":"10.1007/s10753-025-02321-5","DOIUrl":"https://doi.org/10.1007/s10753-025-02321-5","url":null,"abstract":"<p><p>Acute lung injury (ALI) constitutes a major public health concern, with sepsis contributing to up to 50% of ALI cases in the ICU. Androgen receptor (AR) plays a crucial role in immunoregulation. Our study aimed to explore the role of AR and the underlying regulatory mechanisms of AR signaling in septic ALI. We assessed the role of AR in a septic ALI model by manipulating AR expression through orchiectomy, AR knockout, and enzalutamide treatment. Lung injury was evaluated by HE staining and measuring pulmonary vascular leakage. Inflammatory cell infiltration and inflammatory mediator levels were assessed through Immunofluorescence staining and western blot. Additionally, Weighted Gene Co-expression Network Analysis (WGCNA), lentiviral vector, chromatin immunoprecipitation and co-immunoprecipitation were used to elucidate the molecular mechanisms by which AR regulates the secretion of inflammatory cytokines in alveolar macrophages. Male mice exhibited more severe lung injury than female mice in sepsis-induced lung injury. Orchiectomy, AR knockout and enzalutamide treatment suppressed AR activity and significantly alleviated lung injury. AR promotes Fkbp5 expression and NF-κB signaling pathway, thereby enhancing the expression of iNOS and IL-6 in macrophages. Moreover, AR transcription in alveolar macrophages is regulated by hypoxia-inducible factor 1α (HIF1α) signaling. Our study elucidated that inhibiting AR decreases the secretion of inflammatory cytokines in alveolar macrophages and mitigates septic ALI, providing a novel therapeutic approach for septic ALI.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Role of Cholic Acid in the Development of iHFC Diet-induced MASH in TSNO Mice.","authors":"Kana Goto, Koudai Kani, Miyuna Kato, Naoya Igarashi, Yuki Tada, Kaichi Kasai, Mayuko Ichimura-Shimizu, Shiro Watanabe, Koichi Tsuneyama, Yukihiro Furusawa, Yoshinori Nagai","doi":"10.1007/s10753-025-02294-5","DOIUrl":"https://doi.org/10.1007/s10753-025-02294-5","url":null,"abstract":"<p><p>A high-fat/cholesterol/cholate-based (iHFC) diet induces pathological changes in Tsumura-Suzuki non-obese (TSNO) mice, resembling human metabolic dysfunction associated steatohepatitis (MASH), along with advanced liver fibrosis. In this study, we investigated the role of cholic acid (CA) in the development of iHFC diet-induced MASH development. In mice receiving an iHFC diet without CA (CA(-) iHFC diet), both lobular inflammation and fibrosis progression in the liver were attenuated compared to those on the standard iHFC diet. Notably, hepatocyte ballooning was significantly improved in the CA(-) iHFC diet group. The expression levels of genes associated with inflammation and fibrosis were lower in the livers of CA(-) iHFC diet-fed mice compared to those fed the iHFC diet. Furthermore, there were no significant changes in the proportion and number of monocyte-derived macrophages in the livers of CA(-) iHFC diet-fed mice relative to those in the ND (normal diet)-fed group. The co-localization of CD11c⁺ macrophages with collagen fibers in the livers of CA(-) iHFC diet-fed mice did not significantly differ from that of the ND-fed group. Moreover, the CA(-) iHFC-fed mice exhibited a distinct microbial composition relative to both ND- and iHFC-fed mice. Finally, the increase in deoxycholic acid in fecal samples and the reduced hepatic expression of Cyp27a1 and Cyp7a1 induced by the iHFC diet were less in the CA(-) iHFC-fed group. These results suggest that CA modulates iHFC diet-induced MASH development by influencing the accumulation of monocyte-derived macrophages in the liver and shaping the gut microbiota composition and bile acid profile.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of Human FPR2 with AT-RvD1 Resolves Acute Sialadenitis in Vivo.","authors":"Kihoon Nam, Harim Tavares Dos Santos, Frank M Maslow, Daniel J Davis, Tabitha Li Galloway, Laura M Dooley, Patrick T Tassone, Robert P Zitsch, Bryan G Trump, Venkata Yellepeddi, Olga J Baker","doi":"10.1007/s10753-025-02320-6","DOIUrl":"https://doi.org/10.1007/s10753-025-02320-6","url":null,"abstract":"<p><p>Previous studies demonstrated that activation of the mouse G protein-coupled formyl peptide receptor 2 (mFpr2) with aspirin-triggered resolvin D1 (AT-RvD1) blocks pro-inflammatory cytokine signaling while promoting salivary gland (SG) epithelial integrity both in vitro and in vivo. In addition, mice lacking Fpr2 display alterations of SG innate and adaptive immunity. Taken together, these results indicate that Fpr2 activation with AT-RvD1 restores saliva secretion and regulates SG immunity in mice. To demonstrate the value of AT-RvD1 for use in human SG, however, we need to extend the findings above in the direction of clinical use. To this end, the current study investigated whether treatment with AT-RvD1 reduces SG inflammation and restores saliva secretion in an acute sialadenitis mouse model expressing the human formyl peptide receptor 2 (hFPR2) protein. Results indicate that mice carrying the hFPR2 and treated with lipopolysaccharide (LPS) display acute sialadenitis-like features as shown by increased levels of proliferating inflammatory cells, loss of epithelial integrity and reduced saliva secretion. In contrast, when these mice are treated with AT-RvD1, the sialadenitis-like features are drastically reduced as evidenced by a significant decrease in proliferating inflammatory cells as well as restoration of saliva secretion to levels comparable to phosphate buffered saline (PBS)-treated healthy controls. Finally, changes observed in mice carrying the hFPR2 and treated with LPS and AT-RvD1 were comparable to those observed in wild-type mice carrying the mFpr2. Together, these results demonstrate that activation of hFPR2 with AT-RvD1 resolves acute sialadenitis in vivo.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"March6 Protects Against Acute Kidney Injury by Suppressing Renal Tubular Epithelial Cell Ferroptosis Through the Destabilization of P53 and ACSL4 Proteins.","authors":"Jie Feng, Ranran Kong, Yi Yang, Hongjuan Dong, Yurui Guo, Liyi Xie","doi":"10.1007/s10753-025-02319-z","DOIUrl":"https://doi.org/10.1007/s10753-025-02319-z","url":null,"abstract":"<p><p>Acute kidney injury (AKI) progression involves significant contributions from renal tubular epithelial cell ferroptosis. Membrane associated RING finger protein 6 (March6) is implicated in modulating ferroptosis by regulating the stability of related proteins, yet its specific role in tubular epithelial cell ferroptosis and AKI progression remains unknown. This work seeks to clarify the regulatory role of March6 in the ferroptosis of tubular epithelial cells and its involvement in AKI using ischemia-reperfusion injury (IRI)-induced animal models and hypoxia/reoxygenation (H/R)-induced cellular models. Our results demonstrated a significant reduction in March6 expression in renal tissues from IRI mice and H/R cells, accompanied by elevated PTGS2 and reduced GPX4 levels, two ferroptosis marker proteins. Overexpression of March6 in HK-2 cells significantly counteracted Erastin-induced ferroptosis, whereas silencing March6 increased susceptibility. In H/R models, March6 overexpression enhanced cell viability and lowered cell death, reversing ferroptosis-related changes, whereas silencing March6 exhibited the opposite effects. Tubular-specific overexpression of March6 in mice with IRI-induced AKI notably mitigated kidney damage and suppressed ferroptotic changes. Mechanistically, March6 inhibited ferroptosis by accelerating the degradation of key pro-ferroptotic proteins ACSL4 and p53. Co-immunoprecipitation (Co-IP) experiments validated the direct interaction between March6 and p53 or ACSL4. Overexpressing ACSL4 or p53 in March6-overexpressing HK-2 cells markedly reversed March6's protective effects against H/R-induced damage and ferroptosis. Collectively, March6 mitigates ferroptosis in renal tubular epithelial cells by promoting the degradation of ACSL4 and p53, thereby alleviating AKI progression. This study not only uncovers a novel regulatory mechanism of tubular epithelial cell ferroptosis in AKI but also provides a potential therapeutic target for its treatment.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XBP1 Knockdown Alleviates Pyroptosis and Promotes Th17/Treg Imbalance in Periodontitis by Inhibiting the IL-17 Signaling Pathway.","authors":"Lixun Kang, Binglu Shi, Siyu Shen, Kai Ma, Yuanxu Jing, Qi An, Yan Dai","doi":"10.1007/s10753-025-02316-2","DOIUrl":"https://doi.org/10.1007/s10753-025-02316-2","url":null,"abstract":"<p><p>Periodontitis is a long-lasting inflammatory condition that significantly affects people's quality of life. This research focused on examining the function and underlying mechanisms of X-box binding protein 1 (XBP1) in the pathogenesis of periodontitis. In vitro and in vivo models of periodontitis were established using lipopolysaccharide (LPS). The viability and apoptosis of periodontal ligament stem cells (PDLSCs) were assessed using the Cell Counting Kit-8 and flow cytometry assays, respectively. Reverse transcription-quantitative PCR, western blot, and enzyme-linked immunosorbent assays were employed to measure the levels of inflammatory factors and mediators associated with T helper 17 (Th17)/regulatory T cell (Treg) balance, pyroptosis, and the interleukin-17 (IL-17) pathway. Histological and immunohistochemical analyses were conducted to evaluate tissue damage and bone resorption markers. The IL-17 pathway was activated with SR0987 to explore the interactions between XBP1 and IL-17 signaling. XBP1 knockdown reduced apoptosis, pyroptosis, and inflammation, as indicated by lower levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-18) and pyroptosis-related proteins (ASC, GSDMD-N, NLRP3). XBP1 knockdown alleviated tissue damage, inflammatory cell infiltration, and bone destruction in rat models of periodontitis. XBP1 knockdown notably restored the Th17/Treg imbalance by suppressing Th17 differentiation and promoting Treg differentiation. Mechanistically, XBP1 knockdown inhibited the IL-17 signaling pathway, and IL-17Activator SR0987 significantly reversed the beneficial effects of XBP1 knockdown on periodontitis. XBP1 knockdown alleviated periodontitis by inhibiting the IL-17 signaling pathway, implying that XBP1 could serve as a promising therapeutic target for managing periodontal conditions.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Biological Role of the Signal Transducer and Activator of Transcription 1 (STAT1)-miR-221/222-3p-p21 Activated Kinase 1 (PAK1) Axis in Experimental Periodontitis.","authors":"Yun Wu, Yaoting Ji, Rui Mu, Jiawen Pan, Ruixin Fan, Yan Zhao, Shanshan Liang","doi":"10.1007/s10753-025-02314-4","DOIUrl":"https://doi.org/10.1007/s10753-025-02314-4","url":null,"abstract":"<p><p>Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of tooth-supporting tissues. Despite extensive research, the molecular mechanisms underlying its pathogenesis remain incompletely understood. This study aimed to investigate the role and regulatory mechanisms of miR-221/222-3p in experimental periodontitis. The expression of miR-221/222-3p in lipopolysaccharide (LPS)-stimulated periodontal ligament cells (PDLCs) and ligation-induced rat periodontitis were detected by RT-qPCR. miR-221/222-3p agomir were administrated topically in ligation-induced rat periodontitis. The therapeutic function of both miRNAs were assessed by micro-CT, TRAP staining, and immunohistochemistry. The mechanisms of miR-221/222-3p function in periodontitis were determined by cell assays. miR-221-3p and miR-222-3p expression were both downregulated in LPS-stimulated PDLCs and ligation-induced periodontitis rat. In vitro, miR-221-3p and miR-222-3p could alleviate the inflammatory damage of PDLCs upon LPS stimulation. Mechanically, PAK1 is demonstrated as a target gene of miR-221/222-3p. Additionally, STAT1 signaling pathway is activated by LPS treatment and STAT1 could bind to the upstream region of the miR-221/222-3p promoter and repress their expression. In vivo, miR-221/222-3p agomir rescued the alveolar bone loss, alleviated the infiltration of osteoclasts and the expression of inflammatory cytokines of periodontitis rats. Our results revealed a novel STAT1-miR-221/222-3p-PAK1 axis in the initiation and progression of periodontitis. Specific targeting this signaling pathway may provide a new therapeutic avenue for periodontitis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High level expression of OSBPL11 is associated with atherosclerosis and Alzheimer's disease.","authors":"Huayu Zhang, Yanyu Chen, Qian Xu, Xuanshuang Wu, Naiqi He, Zhong Ren, Guixue Wang, Zhihan Tang, Qiong Xiang, Lushan Liu","doi":"10.1007/s10753-025-02252-1","DOIUrl":"https://doi.org/10.1007/s10753-025-02252-1","url":null,"abstract":"<p><p>With the global aging population, the incidence of aging-related diseases such as Alzheimer's disease (AD) and atherosclerosis (AS) is increasing. AS has also been identified as a key risk factor for AD. However, the conjoint molecular mechanisms driving these diseases remain unclear. This study first used bioinformatics analysis to analyze gene expression data in the cortex of AD patients and plaques of AS patients. We identified OSBPL11 as a gene whose expression co-increased under both conditions, and it is expressed in macrophages in AS patients and astrocytes in AD patients. Further validation was conducted through patient sample collection and an ApoE^-/- mouse model. Strikingly, our findings suggest that OSBPL11 plays a role in the development of both AS and AD, and that there is increased co-localization of OSBPL11 with macrophages and astrocytes. This discovery offers new insights into the association between AS and AD and offers a new target for the treatment AS and AD.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LARS1 Promotes Tubular Epithelial Cells Epithelial Mesenchymal Transition in Chronic Kidney Disease by Inhibiting Lipophagy.","authors":"Rui Guo, Mei-Ni Chen, Qian-Hui Lin, Hui-Min Qi, Xiao-Qi Wang, Bing-Yu Li, Shuo Wang, Su-Juan Xu, Yue Zhang, Wei Liu","doi":"10.1007/s10753-025-02313-5","DOIUrl":"https://doi.org/10.1007/s10753-025-02313-5","url":null,"abstract":"<p><p>Tubulointerstitial fibrosis (TIF), a critical pathological hallmark in progressive chronic kidney disease (CKD), may be potentiated by renal lipid metabolism dysregulation and ectopic lipid deposition, though these processes likely exhibit bidirectional interactions with fibrotic progression Lipophagy is a type of selective autophagy that specifically recognizes lipid droplets and is accountable for lipid stability and metabolism. It serves as a link between lipid metabolism and autophagy. It was found that a positive correlation between elevated LARS1 expression and the severity of renal interstitial fibrosis in CKD patients. In Lars1^+/- mice, we observed that the absence of LARS1 significantly reduced lipid deposition and TIF. Mechanistically, stimulation of HK-2 cells with TGF-β1 resulted in LARS1-mediated activation of mTORC1 and suppression of lipophagy, consequently leading to increased lipid accumulation and epithelial mesenchymal transition (EMT) through a defined mechanistic pathway. Collectively, our studies demonstrate that LARS1 plays a pivotal role in renal fibrosis at least in part by inhibiting lipophagy, suggesting that targeting LARS1 may represent a novel therapeutic strategy for patients with CKD.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}