The FASEB Journal最新文献

{"title":"FABP4 Inhibitor Improves Right Ventricular Fibrosis in Metabolic Syndrome- Related Pulmonary Hypertension due to Left Heart Disease in Mice","authors":"Haihua Qiu,&nbsp;Wenjie Chen,&nbsp;Jingyuan Chen,&nbsp;Luo Jun,&nbsp;Yusi Chen,&nbsp;Yingjie Tan,&nbsp;Tianyu Wang,&nbsp;Jiang Li","doi":"10.1096/fj.202500532RR","DOIUrl":"https://doi.org/10.1096/fj.202500532RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Pulmonary hypertension due to left heart disease (PH-LHD) is a prevalent and fatal condition with limited therapeutic options. This study investigates the role and mechanisms of fatty acid binding protein 4 (FABP4) in PH-LHD development. Plasma FABP4 levels were significantly elevated in PH-LHD patients (<i>n</i> = 36) compared to left heart disease patients without PH (noPH-LHD, <i>n</i> = 33) and correlated positively with NT-proBNP. Microarray analysis of GSE236251 identified differentially expressed genes in PH-LHD, with KEGG enrichment highlighting relevant pathways. A PH-LHD mouse model was established using metabolic syndrome (MetS) combined with pressure overload, revealing increased FABP4 expression in plasma, heart, and adipose tissue. Treatment with the FABP4 inhibitor BMS309403 (BMS) significantly reduced MetS-related comorbidities, improved hemodynamics, and alleviated cardiac dysfunction, pulmonary vascular remodeling, myocardial hypertrophy, and fibrosis. BMS also suppressed cardiac fibroblasts (CFs) differentiation and downregulated the Smad3/TGFβ fibrotic signaling pathway in RV tissue, suggesting an anti-fibrotic mechanism. These findings demonstrate that FABP4 serves as both a potential plasma biomarker for PH-LHD severity and a therapeutic target. BMS ameliorates PH-LHD by inhibiting RV fibrosis via modulation of CF differentiation into myofibroblasts, underscoring FABP4 as a promising intervention for PH-LHD.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635583","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":"Aggregation of the Constitutively Active K296E Rhodopsin Mutant Contributes to Retinal Degeneration","authors":"Sreelakshmi Vasudevan,&nbsp;Vivek Prakash,&nbsp;Paul S.-H. Park","doi":"10.1096/fj.202501043R","DOIUrl":"https://doi.org/10.1096/fj.202501043R","url":null,"abstract":"<p>A K296E mutation in rhodopsin causes autosomal dominant retinitis pigmentosa, a progressive retinal degenerative disease. Early characterizations of this mutation indicated that it causes the receptor to be constitutively active, which has been the primary focus when considering the pathogenic mechanism of the mutation thus far. Knockin mice expressing the K296E rhodopsin mutant were generated and characterized to better understand the pathogenic mechanism of the mutation. Knockin mice exhibited progressive retinal degeneration characteristic of retinitis pigmentosa. The K296E rhodopsin mutant mislocalized in photoreceptor cells and, surprisingly, appeared to aggregate, as indicated by the dye PROTEOSTAT, which binds protein aggregates. The propensity of the K296E rhodopsin mutant to aggregate was tested and confirmed in vitro but was dependent on the species background of rhodopsin. The K296E mutation on either murine or human rhodopsin backgrounds exhibited similar propensities to aggregate. The same mutation on a bovine rhodopsin background, however, exhibited a lower propensity to aggregate, indicating this species background does not adequately model the effects of the K296E mutation. In contrast to previous expectations, we demonstrate here that aggregation of the K296E rhodopsin mutant may contribute to photoreceptor cell loss in retinitis pigmentosa.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501043R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635591","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":"Transient Dietary Intervention Induces Healthy Adipose Tissue Expansion and Metabolically Healthy Obesity in Mice","authors":"Eri Wada,&nbsp;Hirotaka Hosono,&nbsp;Miyako Tanaka,&nbsp;Fumi Miyakawa,&nbsp;Kozue Ochi,&nbsp;Hiro Kohda,&nbsp;Shogo Tanno,&nbsp;Reon Shimano,&nbsp;Ayaka Ito,&nbsp;Yasuyuki Kitaura,&nbsp;Kazuya Ichihara,&nbsp;Akinobu Matsumoto,&nbsp;Tomoo Ogi,&nbsp;Noriko Satoh-Asahara,&nbsp;Toyoaki Murohara,&nbsp;Takayoshi Suganami","doi":"10.1096/fj.202501121R","DOIUrl":"https://doi.org/10.1096/fj.202501121R","url":null,"abstract":"<p>As obesity progresses, dynamic tissue remodeling of adipose tissue occurs over time, that is, adipocyte hypertrophy, chronic inflammation, and interstitial fibrosis. Some obese individuals exhibit healthy adipose tissue expansion, characterized by modest inflammation and fibrosis despite adipocyte hypertrophy, resulting in “Metabolically Healthy Obesity (MHO)”. In this study, we investigated the effects of transient weight loss on adipose tissue remodeling during the development of obesity. Male C57BL6/J mice received various types of transient weight loss treatments during diet-induced obesity. A 2-week weight loss intervention during the inflammatory phase promoted healthy adipose tissue expansion, reduced ectopic lipid accumulation, and improved glucose metabolism. In contrast, protocols with shorter duration and delayed intervention, failed to induce MHO. Since serum concentrations of ketone bodies were elevated during weight loss, we examined the effects of hyperketonemia on obesity-induced adipose tissue remodeling. Transient treatment with 1,3-butanediol (BD), which increased serum ketone body concentrations to levels similar to those observed during weight loss, induced healthy adipose tissue expansion and reduced hepatic steatosis even during continuous high-fat diet (HFD) feeding. Ketone bodies effectively suppressed activation of adipose tissue fibroblasts in vivo and in vitro. This study provides evidence that an appropriate dietary intervention can promote healthy adipose tissue expansion in mice, even after the regaining of weight, thereby leading to MHO. As the underlying mechanism, our data revealed a key role for ketone bodies in suppressing activation of adipose tissue fibroblasts. This study paves the way for nutritional approaches to induce MHO.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501121R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635584","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":"SARM1 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Enhancing NAD+ Metabolism","authors":"Hui-Ting Shi,&nbsp;Guo-Jun Zhao,&nbsp;Si-Jia Liu,&nbsp;Bin-Bin Du,&nbsp;Li-Li Xiao,&nbsp;Zhen Huang,&nbsp;Dian-Hong Zhang,&nbsp;Lei-Ming Wu,&nbsp;Yan-Yu Lu,&nbsp;Qi-Guang Du,&nbsp;Er-Kui Wang,&nbsp;Yan-Zhou Zhang","doi":"10.1096/fj.202500486RR","DOIUrl":"https://doi.org/10.1096/fj.202500486RR","url":null,"abstract":"<p>Heart failure (HF) represents the terminal phase in the progression of numerous clinical conditions, with high mortality and significant economic impact. Nicotinamide adenine dinucleotide (NAD⁺) is a crucial cofactor in HF pathogenesis. Sterile alpha and TIR motifs of 1 (SARM1) is an intracellular NAD⁺ hydrolase that plays a well-defined role in axonal degeneration and neuronal injury, but its role in HF is unclear. Consequently, our study sought to elucidate the role of SARM1 in the context of HF. We generated in vivo and in vitro HF models using transverse aortic constriction in mice and phenylephrine stimulation of neonatal rat cardiomyocytes (NRCMs) to study the effects of <i>Sarm1</i> gene deletion and SARM1 overexpression. Our findings revealed a significant increase in SARM1 expression in HF and demonstrated that SARM1 suppression could mitigate adverse cardiac remodeling and dysfunction, whereas overexpression of SARM1 had the opposite effects. Subsequent investigations indicated that SARM1 functions in reducing cardiac NAD⁺ levels, impairing mitochondrial bioenergetics, and exacerbating HF progression. Conversely, supplementation with nicotinamide mononucleotide (NMN) ameliorated hypertrophy in NRCMs overexpressing SARM1 following phenylephrine induction. SARM1 is a key factor in HF by reducing intracellular NAD⁺ levels, making it a potential target for HF therapy.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500486RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624551","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":"RasGRP4 Exacerbates Diabetic Kidney Fibrosis via Aloxe3-Mediated Oxidative Stress and Scar-Associated Macrophage Activation","authors":"Binshan Zhang,&nbsp;Jian Wang,&nbsp;Ashanjiang Aniwan,&nbsp;Saijun Zhou,&nbsp;Ying Li,&nbsp;Lihua Wang,&nbsp;Yunqi Wu,&nbsp;Zhongli Wang,&nbsp;Li Zhang,&nbsp;Yao Lin,&nbsp;Pei Yu","doi":"10.1096/fj.202501964R","DOIUrl":"https://doi.org/10.1096/fj.202501964R","url":null,"abstract":"<p>Renal fibrosis is an irreversible pathological feature of diabetic kidney disease (DKD), and targeting macrophage phenotype is a promising strategy to prolong it. Ras guanine nucleotide-releasing protein 4 (RasGRP4) is a signaling protein involved in immune regulation. This study aimed to investigate how RasGRP4 contributes to kidney fibrosis by regulating scar-associated macrophages (SAM). Kidney biopsy tissues and peripheral blood mononuclear cells (PBMCs) were collected from diabetic patients. Findings indicated that RasGRP4-expressing macrophages infiltrated the kidneys more extensively, and RasGRP4 levels in PBMCs rose with the progression of proteinuria. The DKD model was constructed using RasGRP4 knockout mice to assess the impact of RasGRP4 on renal interstitial fibrosis. Transcriptomic sequencing of PBMCs revealed that RasGRP4^−/− reduced the expression of the downstream gene Arachidonate lipoxygenase 3 (Aloxe3), which colocalized with RasGRP4 in macrophages. Aloxe3 was found to enhance oxidative stress, promoting the infiltration of Trem2⁺SPP1⁺SAM and the release of fibrotic mediators. In vitro experiments showed that silencing RasGRP4 or Aloxe3 in macrophages downregulated oxidative stress and fibrosis markers associated with SAM. This study is the first to identify RasGRP4 as a key mediator in diabetic kidney fibrosis, acting through Aloxe3-mediated oxidative stress and facilitating SAM activation, thus offering new therapeutic insights for DKD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501964R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144624884","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":"VGF-Derived TLQP-21 Ameliorates Tumor Progression, Pain, and Depression-Like Behaviors in an Orthotopic Mouse Model of Pancreatic Ductal Adenocarcinoma","authors":"Shuying Huang,&nbsp;Pei Xia,&nbsp;Qiuyi Chen,&nbsp;Yixiu Zeng,&nbsp;Xin Cheng,&nbsp;Qianyi Cao,&nbsp;Wenbao Cai,&nbsp;Yuying Yang,&nbsp;Yang Ouyang,&nbsp;Xinyu Wang,&nbsp;Yiyi Li,&nbsp;Jun Chen,&nbsp;Wei-Jye Lin,&nbsp;Xiaojing Ye","doi":"10.1096/fj.202500400R","DOIUrl":"https://doi.org/10.1096/fj.202500400R","url":null,"abstract":"<div>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer associated with severe pain and depression. Neuropeptide VGF (non-acronymic) exhibits robust expression in the pancreas and brain, known for its modulatory roles in metabolic homeostasis, nociception, and depression-like behaviors. Despite elevated VGF expression being linked to poor prognosis in various cancers, its specific role in PDAC remains unexplored. By combining bioinformatic analysis of clinical datasets with experimental validations, we uncover that high VGF expression correlates with improved survival in PDAC patients. Notably, the administration of TLQP-21, a C-terminal peptide derived from VGF, significantly reduces tumor size and enhances the therapeutic efficacy of gemcitabine, resulting in a marked increase in overall survival in an orthotopic mouse model of PDAC. Mechanistically, TLQP-21 suppresses the tumor-promoting effects of tumor-associated macrophages through complement receptors C3aR1 and C1qBP. Additionally, TLQP-21 alleviates depression-like behaviors, allodynia, and muscle wasting in PDAC mice. Collectively, these findings demonstrate the dual efficacy of TLQP-21 in inhibiting tumor growth and mitigating nociceptive and psychiatric symptoms, highlighting the potential of TLQP-21 as a therapeutic option for PDAC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615118","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":"RORβ Deficiency Inhibits Endochondral Ossification in Mice by Mediating the HIF-1α/VEGFA Signaling Pathway","authors":"Yifan Zhang,&nbsp;Xingfu Bao,&nbsp;Jun Ma,&nbsp;Linhe Lv,&nbsp;Min Hu,&nbsp;Xiaoxi Wei","doi":"10.1096/fj.202501073RR","DOIUrl":"https://doi.org/10.1096/fj.202501073RR","url":null,"abstract":"<p>Retinoic acid receptor-related orphan receptor beta (RORβ) is a ligand-dependent transcription factor essential for bone metabolism. While RORβ negatively regulates osteoblast differentiation and contributes to age-related or postmenopausal osteoporosis, its role in early skeletal development remains unclear. This study developed a <i>Rorβ</i> gene knockout (KO) mouse model using CRISPR/Cas9 to investigate its effects on endochondral ossification. At 4 weeks, <i>Rorβ</i> KO mice exhibited dwarfism and early-onset osteoporosis, with reduced femur length (−8.84%), lower cortical and trabecular bone mass, and impaired bone quality. The trabecular bone was fragile, with reduced surface osteoblasts and impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Chondrogenesis was also disrupted, evidenced by a thinner growth plate, fewer chondrocytes, and a disorganized hypertrophic zone (HZ). The expressions of proliferation (Ki67) and hypertrophic differentiation (Collagen X) markers were significantly reduced. Mechanistically, RORβ deficiency downregulated hypoxia-inducible factor 1-alpha (HIF-1α) and its downstream target vascular endothelial growth factor A (VEGFA) in both the pre-hypertrophic zone (PHZ) of the growth plate and BMSCs. These findings identify RORβ as a critical regulator of endochondral ossification, linking its loss to skeletal defects via impaired HIF-1α/VEGFA signaling. This study provides insights into potential therapeutic strategies for skeletal diseases such as skeletal dysplasia.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501073RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615121","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":"Transcriptomics and Targeted Metabolomics Reveal That CES1 Ablation in Macrophages Confers a Distinct Inflammatory Phenotype Involving Altered Interleukin-1β, Citrate, and Lipid Levels","authors":"Oluwabori Adekanye,&nbsp;Abdolsamad Borazjani,&nbsp;Maggie E. Phillips,&nbsp;Matthew K. Ross","doi":"10.1096/fj.202500753R","DOIUrl":"https://doi.org/10.1096/fj.202500753R","url":null,"abstract":"<div>\u0000 \u0000 <p>Inflammation is beneficial when the initial threat is neutralized and the response is self-limiting, but when unresolved, it is often deleterious. Macrophages are immune cells that differentiate into classically activated (M1) and alternatively activated (M2) cells that promote and attenuate inflammation, respectively. Carboxylesterase 1 (CES1) is a serine hydrolase that metabolizes neutral lipids, including triacylglycerols (TAGs) and others. THP-1 macrophages with deficient CES1 expression (CES1KD cells) have a distinctly foamy phenotype as compared to CES1-expressing THP-1 macrophages (control cells), which is due to greater quantities of TAG-containing lipid droplets. CES1KD cells also produce more IL-1β and PGE2 than control cells following lipopolysaccharide (LPS) stimulation, with no evidence of pyroptosis. Here, we examined the proinflammatory phenotype of CES1KD cells in more detail by examining their transcriptomic and inflammatory signatures. Based on RNA-seq data, we observed a strong concordance between the differentially expressed genes in baseline (unstimulated) CES1KD cells and those in control cells treated with LPS/IFNγ (<i>r</i> = 0.728). This is consistent with the altered metabolite profiles that were observed in CES1KD cells (elevated levels of citrate, prostaglandins, and TAGs) and increased expression of HIF1α, pro-caspase-1, and pro-IL-1β that together signify a proinflammatory phenotype. <i>Gene Ontology</i>, <i>KEGG</i>, and <i>Reactome</i> analyses of CES1KD cells in their baseline state revealed the enrichment of upregulated pathways involved in antibacterial and antiviral defense and inflammasome signaling comparable to those seen in control cells stimulated with LPS/IFNγ. NLRP3 inflammasome-dependent production of IL-1β was much more pronounced in CES1KD cells and did not require an LPS priming step. We conclude that CES1KD macrophages, even under baseline conditions (M0) exhibit an immunophenotype like that of M1 control cells. These findings suggest that active CES1 may negatively regulate macrophage inflammatory immune responses, and thus enhancing its activity might be a novel strategy to attenuate inflammation.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615119","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":"The Kinesin Motor Kif9 Disrupts Primary Cilia Length by Mispositioning Centriolar Satellites","authors":"Juan Jesus Vicente,&nbsp;Jacob Weiss,&nbsp;Michael Wagenbach,&nbsp;Linda Wordeman","doi":"10.1096/fj.202501115R","DOIUrl":"https://doi.org/10.1096/fj.202501115R","url":null,"abstract":"<p>Primary cilia are nonmotile, microtubule-based structures on the surface of most vertebrate cells, acting as sensory hubs to regulate cellular responses. Their formation, maintenance, and disassembly are tightly regulated, with dysfunction linked to diseases like ciliopathies, cancer, and neurological disorders. Centriolar satellites (CS), membrane-less granules around the centrosome, are involved in protein trafficking to and from the centrosome and centrosomal function, and regulate primary cilia. We show that Kif9 loss causes CS aggregation near the centrosome, leading to defects in cilia length and altering the levels of key primary cilia proteins like TALPID3, CEP131, CEP170, and CEP290.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501115R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615122","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":"Salvianolic Acid B Attenuates Ferroptosis in Acute Kidney Injury by Targeting PRDX5","authors":"Yan Tao,&nbsp;Shengjun Fu,&nbsp;Jianzhong Lu,&nbsp;Beitang Fu,&nbsp;Shanhui Liu,&nbsp;Lanlan Li","doi":"10.1096/fj.202500258RR","DOIUrl":"https://doi.org/10.1096/fj.202500258RR","url":null,"abstract":"<p>Acute kidney injury (AKI) is a common side effect of the chemotherapy agent cisplatin, and ferroptosis serves as the primary mechanism underlying cell death in renal tubular epithelium in such cases. Salvianolic acid B (SAB), a compound derived from <i>Salvia miltiorrhiza</i>, has demonstrated promising anti-inflammatory and antioxidant properties. However, its impact on ferroptosis in the context of AKI remains to be fully explored. In this study, we utilized cisplatin-induced and folic acid-induced AKI models to investigate the protective mechanisms of SAB on renal tissue and tubular epithelial cell injury. The impact of SAB on renal cell ferroptosis was thoroughly examined and confirmed in both AKI models. To predict the potential mechanism through which SAB regulates ferroptosis, we employed an online target prediction database and subsequently verified the specific target proteins involved. Furthermore, we used drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking techniques to assess the binding capacity of SAB to the target protein. Our results reveal that SAB alleviated cisplatin- and folic acid-induced renal dysfunction in vivo and improved cisplatin-induced HK-2 cell injury. Mechanistically, SAB targeted and bound to PRDX5, enhancing its redox activity, which in turn potentiated the inhibitory effect of SLC7A11 and GPX4 on cisplatin-induced ferroptosis. Silencing PRDX5 in HK-2 cells could partially abrogate the protective effect of SAB. These results provide strong evidence for the potential of SAB in the treatment of AKI.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 14","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500258RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615120","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}