{"title":"Macrophages in Focus: Key Drivers and Therapeutic Opportunities in Diabetic Kidney Disease.","authors":"Hui Zhao, Jia Guo","doi":"10.7150/ijbs.112737","DOIUrl":"10.7150/ijbs.112737","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD), a common microvascular complication of diabetes, has emerged as the leading cause of end-stage renal disease (ESRD), with its prevalence increasing annually, thereby constituting a global epidemiological crisis. Despite this, the search for effective therapeutic strategies remains challenging, underscoring the urgent need for innovative treatments. In recent years, numerous studies have highlighted the role of inflammation in DKD progression, with fibrosis serving as a critical mechanism driving DKD towards ESRD. Intervening in these core processes may reveal new avenues for the etiology and management of DKD. Macrophages, immune cells derived from monocytes, possess phagocytic and digestive functions and play integral roles in tissue and organ development, homeostasis, as well as tissue repair and regeneration. Emerging research suggests that macrophages are crucial in DKD progression and renal injury, thus attracting significant academic attention. This review highlights the role and mechanisms of macrophages in the inflammatory and fibrotic processes in DKD. It also explores current therapeutic approaches targeting macrophages. In light of recent research, we propose that macrophages-focused interventions present a promising therapeutic avenue for DKD.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4647-4662"},"PeriodicalIF":10.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788946","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":"SIRT4-Mediated Deacetylation of PRDX3 Attenuates Liver Ischemia Reperfusion Injury by Suppressing Ferroptosis.","authors":"Qiwen Yu, Dongjing Yang, Binli Ran, Jie Pan, Yaodong Song, Mengwei Cui, Qianqian He, Chaopeng Mei, Haifeng Wang, Huihui Li, Guanghui Li, Yinuo Meng, Fazhan Wang, Wenzhi Guo, Changju Zhu, Sanyang Chen","doi":"10.7150/ijbs.114510","DOIUrl":"10.7150/ijbs.114510","url":null,"abstract":"<p><p>Liver ischemia-reperfusion injury (LIRI) is an important cause of the clinical prognosis of liver transplantation. Despite Sirtuin 4 (SIRT4) is involved in various post-translational modifications, its role in LIRI is unclear. This research aimed to investigate the influence of SIRT4 on the pathogenesis of LIRI. To this end, SIRT4 knockout (KO) and liver-specific overexpression mice, as well as alpha mouse liver 12 (AML12) cells, were employed. We showed that SIRT4 expression was downregulated in mice with LIRI or AML12 cells exposed to hypoxia-reoxygenation (H/R) injury, as well as in the liver tissue of liver transplant patients. SIRT4 KO exacerbated liver injury and ferroptosis; conversely, liver-specific SIRT4 overexpression in mice produced the opposite results. Furthermore, the ferroptosis inhibitor ferrostatin-1 mitigated the exacerbation of liver injury and ferroptosis caused by SIRT4 KO. Mechanistically, SIRT4 interacted with peroxiredoxins 3 (PRDX3) and deacetylated it at lysine 92, leading to the inhibition of ferroptosis. Furthermore, the protective effect of SIRT4 on LIRI was dependent on PRDX3 deacetylation at lysine 92. Additionally, liver-targeted lipid nanoparticles (LNPs)-sirt4 mRNA alleviated LIRI and ferroptosis in mice. Taken together, our findings highlight the SIRT4-PRDX3 axis as a key regulator and potential therapeutic target for LIRI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4663-4682"},"PeriodicalIF":10.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788951","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}
Xin Lai, Aimin Wu, Yao Liu, Chen Liu, Junzhou Chen, Ke Gu, Bing Yu, Hui Yan, Junqiu Luo, Ping Zheng, Jie Yu, Daiwen Chen
{"title":"Ferritinophagy activation states determine the susceptibility to ferroptosis of macrophages in bone marrow and spleen.","authors":"Xin Lai, Aimin Wu, Yao Liu, Chen Liu, Junzhou Chen, Ke Gu, Bing Yu, Hui Yan, Junqiu Luo, Ping Zheng, Jie Yu, Daiwen Chen","doi":"10.7150/ijbs.114545","DOIUrl":"10.7150/ijbs.114545","url":null,"abstract":"<p><p>Macrophages exhibit heterogeneity due to their presence in different tissues that have distinct cell fates. Ferroptosis is one type of cellular fate, but the sensitivity of different types of macrophages to ferroptosis and the associated molecular mechanisms are not clear. This study explored the ferroptosis sensitivity of bone marrow and splenic macrophage, focusing on the contribution of ferritinophagy. We found that bone marrow M2 macrophages were more susceptible to ferroptosis, which was attributed to their lower solute carrier family 40 member 1 (SLC40A1) and ferritin heavy/light chain (FTH/L) expression and higher labile iron levels compared to those of splenic macrophages. Further, ferritinophagy activation, particularly in M2 macrophages, was identified as the primary cause of increased labile iron levels, as evidenced by experiments using autophagic flux modifiers and RAW264.7 cells with autophagy related 5 (ATG5) and nuclear receptor coactivator 4 (NCOA4) knockdown and NCOA4 knockout. These results provide a new direction for further understanding the heterogeneity and functionality of macrophages, and offers innovative treatments for a variety of health issues in which macrophage regulation plays a critical role.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4567-4585"},"PeriodicalIF":10.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788873","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}
Seo Young Woo, Min Kyu Park, A Ra Kho, Hyun Wook Yang, Hyun Ho Jung, Jaewoo Shin, Minwoo Lee, Ha Na Kim, Jae Young Koh, Bo Young Choi, Sang Won Suh
{"title":"Amlexanox Ameliorates Traumatic Brain Injury by Restoring Autophagy-Lysosomal Function via cAMP Signaling Modulation.","authors":"Seo Young Woo, Min Kyu Park, A Ra Kho, Hyun Wook Yang, Hyun Ho Jung, Jaewoo Shin, Minwoo Lee, Ha Na Kim, Jae Young Koh, Bo Young Choi, Sang Won Suh","doi":"10.7150/ijbs.111216","DOIUrl":"10.7150/ijbs.111216","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) disrupts cellular homeostasis through lysosomal dysfunction, oxidative stress, and impaired autophagy, contributing to neuronal degeneration. Despite advances in our understanding of these mechanisms, effective therapeutic options remain limited. This study investigates amlexanox (AMX), a broad-spectrum phosphodiesterase (PDE) inhibitor, as a potential treatment for TBI-induced neuronal damage. AMX not only increases cyclic adenosine monophosphate (cAMP) levels by inhibiting multiple PDE isoforms but also exhibits anti-inflammatory properties by suppressing pro-inflammatory cytokine production and glial activation via NF-κB and STAT3 pathway inhibition. This dual pharmacological profile suggests a multifaceted therapeutic potential for brain injury. High-throughput screening of an FDA-approved drug library identified AMX as an agent that restores lysosomal acidity through protein kinase A (PKA) activation in primary neuron cultures. <i>In vitro</i> scratch assays demonstrated that AMX enhances lysosomal function, reduces dendritic loss, and promotes neuronal survival. Using a controlled cortical impact model, <i>in vivo</i> experiments revealed that AMX alleviates oxidative and endoplasmic reticulum stress, suppresses neuroinflammation by reducing microglial and astrocytic activation, and preserves neuronal viability in the hippocampus. Behavioral assessments confirmed significant improvements in cognitive and neurological deficits following TBI. These findings establish that AMX is a promising therapeutic agent that restores lysosomal function and mitigates TBI-induced neuronal damage through multi-target PDE inhibition and anti-inflammatory actions.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4467-4484"},"PeriodicalIF":10.0,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788868","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":"Fibroblast Growth Factor 19 Disrupts Cartilage Development Via the FGFR4/β-catenin Axis.","authors":"Hao Chen, Yujia Cui, Jiazhou Li, Mengmeng Duan, Caixia Pi, Xuedong Zhou, Jing Xie","doi":"10.7150/ijbs.110133","DOIUrl":"10.7150/ijbs.110133","url":null,"abstract":"<p><p>Fibroblast growth factor 19 (FGF19) has received increasing attention in metabolic disorders of the skeletal system, but its role in cartilage development is poorly understood. In the present study, we used <i>ex vivo</i> metatarsal organ model for nascent cartilage and an AAV-FGF19 overexpression model for adolescent growth plates to demonstrate the influence of FGF19 on cartilage development. We found that FGF19 could impair chondrocyte maturation at the neonatal stage and decrease growth plate thickness at the adolescent stage. FGF19 reduces chondrogenic differentiation of mesenchymal stem cells and the chondrocyte maturation via downregulation of Wnt/β-catenin signalling. FGF19-mediated chondrocyte maturation and cartilage differentiation require the participation of FGFR4 with the aid of β-klotho (KLB). FGF19 signalling entered the cytoplasm through FGFR4, activated the expression of SFRP1, WIF1 and DKK2, which are antagonists of β-catenin signalling, and hindered chondrocyte proliferation and cartilage growth. This study demonstrates for the first time that FGF19 inhibits cartilage development through the FGFR4/β-catenin axis, providing evidence for the vital role of FGF19 in growth plate chondrogenesis and endochondral ossification.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4428-4449"},"PeriodicalIF":10.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788874","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":"Nanog overexpression enhances the therapeutic efficacy of ADMSCs in AMI rats via the upregulation of JAK/STAT3 signaling and cyclin-mitochondrial expression.","authors":"Hsu-Ting Yen, David Kwan Ru Huang, Xian-Wu Lan, Jui-Ning Yeh, Yi-Ling Chen, Chi-Ruei Huang, Yi-Ting Wang, Hon-Kan Yip, Pei-Hsun Sung, Sheung-Fat Ko","doi":"10.7150/ijbs.112824","DOIUrl":"10.7150/ijbs.112824","url":null,"abstract":"<p><p><b>Background:</b> This study investigated whether Nanog-overexpressing adipose-derived mesenchymal stem cells (Nanog<sup>OE</sup>-ADMSCs) are superior to unmodified ADMSCs in improving the left ventricular ejection fraction (LEVF) in acute myocardial infarction (AMI) patients. <b>Methods:</b> We utilized silencing and overexpression of Nanog gene in ADMSCs and performed a wound healing assay/transwell migration assay/MTT cell viability assay/left coronary artery ligation for AMI induction. Additionally, we categorized the cells into three classes [i.e., (ADMSCs and Nanog<sup>OE</sup>-ADMSCs); A<sub>1</sub> (ADMSCs)/A<sub>2</sub> (ADMSCs + CoCl<sub>2</sub>)/A<sub>3</sub> (Nanog<sup>OE</sup>-ADMSCs + CoCl<sub>2</sub>)/A<sub>4</sub> (siRNA-Nanog-ADMSCs) + CoCl<sub>2</sub>); B<sub>1</sub> (ADMSCs)/B<sub>2</sub> (ADMSCs + H<sub>2</sub>O<sub>2</sub>)/B<sub>3</sub> (Nanog<sup>OE</sup>-ADMSCs + H<sub>2</sub>O<sub>2</sub>)/B<sub>4</sub> (siRNA-Nanog gene in ADMSCs + H<sub>2</sub>O<sub>2</sub>)], and the rats (n=50) were evenly divided into Groups 1 (sham-operated control)/2 (AMI)/3 (AMI+ADMSCs)/4 (AMI+Nanog<sup>OE</sup>-ADMSCs)/5 (AMI+siRNA-Nanog-ADMSCs). The hearts were harvested on Day 35. <b>Results:</b> <i>In vitro</i> experiments revealed significantly higher ATP, relative mitochondrial DNA/Nonog gene expression, mitochondrial cytochrome C+ cell, angiogenesis and exosome-specific marker (Alix/CD81/CD63/CD9) levels in Nanog<sup>OE</sup>-ADMSCs than in ADMSCs. The cell viability, wound healing, and migration were highest in A1, lowest in A4, and significantly greater in A3 than in A2, whereas early/late apoptosis and intracellular and mitochondrial ROS displayed the opposite pattern of cell viability among the groups (all <i>P<</i>0.001). Additionally, the proteins expressions of phosphorylation (p) of the PI3K/Akt/mTOR, p-JAK2/p-STAT3, and Ras/Raf/MEK<sub>1/2</sub>/ERK<sub>1/2</sub> signaling pathways were highest in A3, lowest in A4 and significantly greater in A1 than in A2 (all <i>P<</i>0.001). The levels of cell cycle proteins and mitochondrial electron transport train (ETC) complex I/II/III/IV components exhibited identical patterns as PI3K/Akt/mTOR among the groups B1 to B4 (all <i>P<</i>0.001). On Day 35, the LVEF was highest in Group 1, lowest in Group 2, significantly greater in Group 4 than in Groups 3 and 5, and significantly greater in Group 3 than in Group 5, with the opposite pattern for the LV remodeling index, infarct and fibrosis areas, and LV chamber size (all <i>P <</i> 0.0001). The p-AK/p-STAT3, p-PI3K/p-Akt/p-mTOR, and Ras/Raf/MEK<sub>1/2</sub>/ERK<sub>1/2</sub> protein levels displayed the same pattern as the LVEF among the groups (all <i>P <</i> 0.001). <b>Conclusion:</b> Nanog<sup>OE</sup>-ADMSCs rescued LVEF by upregulating JAK/STAT3-mediated cell proliferation/cell stress pathways and accelerating the cell cycle.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4450-4466"},"PeriodicalIF":10.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788947","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}
Lei Li, Zixi Wang, Bohan Ma, Qi Ye, Yuzeshi Lei, Mingming Lu, Leihong Ye, Jialu Kang, Wenyue Huang, Shan Xu, Ke Wang, Yule Chen, Jing Liu, Yang Gao, Chenji Wang, Jian Ma, Lei Li
{"title":"BAY11-7082 Targets RNF25 to Reverse TRIP4 Ubiquitination-dependent NF-κB Activation and Apoptosis Resistance in Renal Cell Carcinoma.","authors":"Lei Li, Zixi Wang, Bohan Ma, Qi Ye, Yuzeshi Lei, Mingming Lu, Leihong Ye, Jialu Kang, Wenyue Huang, Shan Xu, Ke Wang, Yule Chen, Jing Liu, Yang Gao, Chenji Wang, Jian Ma, Lei Li","doi":"10.7150/ijbs.115032","DOIUrl":"10.7150/ijbs.115032","url":null,"abstract":"<p><p>NF-κB pathway dysregulation, a common driver of therapy resistance in cancer, promotes survival by suppressing apoptosis. While the anti-apoptotic role of NF-κB is recognized, the molecular mechanisms underlying this process remain poorly defined. Here, we identify the E3 ubiquitin ligase RNF25 as a key mediator of NF-κB-dependent apoptosis resistance in renal cell carcinoma cells, enabling evasion of multiple targeted therapies. Mechanistically, RNF25 binds TRIP4 and catalyzes its non-degradative ubiquitination at lysine 135, disrupting TRIP4-p65 interactions. This modification liberates p65 to activate NF-κB signaling, upregulating anti-apoptotic effectors (e.g., <i>cIAP2</i>, <i>Bcl-2</i>). We further demonstrate that the NF-κB inhibitor BAY11-7082 directly interacts with RNF25, reversing its pro-survival effects and restoring apoptosis sensitivity. Our findings establish RNF25 as a druggable orchestrator of therapy resistance through NF-κB pathway modulation and propose pharmacological targeting of RNF25 by BAY11-7082 as a strategy to overcome apoptosis resistance in renal malignancies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4410-4427"},"PeriodicalIF":10.0,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788869","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}
Yan Zhong, Jingfeng Liu, Wenwen Lin, Tian Peng, Lingfang Gao, Lan Shen, Ping Wang, Zhiyan Hu, Ting Long, Zuguo Li, Jingquan Liu
{"title":"Stabilization of OLFML1 via m<sup>6</sup>A Reader IGF2BP3 Drives CSC Characteristics Through Hedgehog Pathway Activation in CRC.","authors":"Yan Zhong, Jingfeng Liu, Wenwen Lin, Tian Peng, Lingfang Gao, Lan Shen, Ping Wang, Zhiyan Hu, Ting Long, Zuguo Li, Jingquan Liu","doi":"10.7150/ijbs.111032","DOIUrl":"10.7150/ijbs.111032","url":null,"abstract":"<p><p>Colorectal cancer (CRC) progression is closely associated with cancer stemness, which contributes to poor prognosis and therapeutic resistance. This study identifies OLFML1 as a key target accounting for CRC progression. High expression of OLFML1 promotes CRC cell proliferation and cancer stemness. As for mechanism study, we further revealed that IGF2BP3 as a critical up-stream regulator of OLFML1. Our study indicated that IGF2BP3 stabilizes OLFML1 mRNA through m<sup>6</sup>A modification, thereby enhancing its expression. In addition, IGF2BP3 prevents OLFML1 degradation via the ubiquitin-proteasome pathway. Clinically, this study demonstrated a positive association between IGF2BP3 and OLFML1 in CRC patient samples. High co-expression of IGF2BP3 and OLFML1 was significantly correlated with larger tumor size and advanced T stage. These findings highlight the IGF2BP3/OLFML1 axis as a potential driver of CRC stemness and Hedgehog pathway activation, offering promising prognostic and therapeutic targets for CRC management.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4334-4352"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788952","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}
Zhangzhen Du, Yongqi Zhao, Ke Zhang, Qiaozhen Qin, Changyi Luo, Jiamei Wu, Heyang Zhang, Shuirong Liu, Zhenhua Xu, Jing Zheng, Shuli Fan, Xiaoxia Jiang, Xu Li, Yan Wang
{"title":"Undercarboxylated OCN Inhibits Chondrocyte Hypertrophy and Osteoarthritis Development through GPRC6A/HIF-1α Cascade.","authors":"Zhangzhen Du, Yongqi Zhao, Ke Zhang, Qiaozhen Qin, Changyi Luo, Jiamei Wu, Heyang Zhang, Shuirong Liu, Zhenhua Xu, Jing Zheng, Shuli Fan, Xiaoxia Jiang, Xu Li, Yan Wang","doi":"10.7150/ijbs.105560","DOIUrl":"10.7150/ijbs.105560","url":null,"abstract":"<p><p>Initial investigations established osteocalcin (OCN) as a pivotal factor in bone formation. Fully carboxylated osteocalcin (cOCN) exhibits a high affinity for hydroxyapatite within the bone matrix, yet under specific physiological conditions, it may undergo decarboxylation, thereby acquiring endocrine regulatory capabilities. Recent findings suggest a potential protective role for undercarboxylated osteocalcin (ucOCN) beyond bone, influencing various systems, including the brain, pancreas, muscle, and gonads, where its effects are well established. Although increased intracellular OCN expression is often considered a marker of osteoarthritis (OA) and chondrocyte hypertrophy, the specific role of extracellular ucOCN in chondrocytes remains largely unexplored and has received little attention, especially regarding its potential to modulate OA-related changes. This study used OCN knockout (OCN<sup>-/-</sup>) mice and found that OCN absence increased collagen type X (COL10) and matrix metalloproteinase 13 (MMP13) expression in chondrocytes, despite a lack of severe OA phenotype. A declining trend of ucOCN in synovial fluid was observed in arthritis models and OA patients, suggesting a role in OA progression. Elevation of ucOCN levels led to the downregulation of COL10a1 and MMP13 expression, accompanied by a marked improvement in cartilage integrity in murine models of arthritis. Additionally, ucOCN regulated the G protein-coupled receptor class C group 6 member A (GPRC6 A) and Hypoxia-inducible factor 1-alpha (HIF-1α) pathways, promoting TIMP3 expression and autophagy in chondrocytes, indicating distinct molecular mechanisms behind its protective effects.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4353-4373"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788935","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}
Shaowan Xu, Xin Peng, Zhenfang Wang, Chenchen Le, Xiangkun Wu, Zhicheng Zeng, Sisi Zeng, Ceng Zhang, Mingxing Qiu, Xin Zou, Hongxia Zhang, Feifei Wang, Wei Kang, Yanqing Ding, Li Liang
{"title":"FABP7-mediated lipid-laden macrophages drive the formation of pre-metastatic niche and liver metastasis.","authors":"Shaowan Xu, Xin Peng, Zhenfang Wang, Chenchen Le, Xiangkun Wu, Zhicheng Zeng, Sisi Zeng, Ceng Zhang, Mingxing Qiu, Xin Zou, Hongxia Zhang, Feifei Wang, Wei Kang, Yanqing Ding, Li Liang","doi":"10.7150/ijbs.110750","DOIUrl":"10.7150/ijbs.110750","url":null,"abstract":"<p><p>Abnormal metabolism processes play a crucial role in the establishment of the pre-metastatic niche (PMN) and the subsequent metastasis to distant organs. However, the precise mechanisms underlying the lipid metabolic reprogramming of macrophages within the liver PMN remain elusive. In this study, we observed an upregulation of fatty acid-binding protein 7 (FABP7) in liver macrophages, which resulted in the accumulation of lipid droplets (LDs) within the PMN of colorectal cancer and pancreatic ductal adenocarcinoma. This accumulation was found to be mediated by the HIF-1α-induced expression of FABP7, which in turn enhanced DGAT1 activity in these macrophages. Furthermore, FABP7-induced lipid-laden macrophages were observed to deliver lipids to CD8<sup>+</sup> T and tumor cells via exosomes. This process led to CD8<sup>+</sup> T cell dysfunction and increased tumor cell proliferation through metabolic reprogramming. Importantly, genetic knockout or pharmacological inhibition of FABP7 reduced liver metastasis. Our findings reveal a novel mechanism involving FABP7-mediated LD in macrophages that contributes to liver PMN formation and metastasis. This suggests that targeting FABP7 may offer prognostic and therapeutic potential in addressing liver metastasis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 10","pages":"4388-4409"},"PeriodicalIF":10.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788872","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}