Experimental cell research最新文献

{"title":"BIRC3 Promotes BYSL Ubiquitination and Degradation and Attenuates WNT/β-Catenin Signaling and Malignant Phenotypes in Lung Squamous Cell Carcinoma.","authors":"Jianyi Ding, Yangjun Xu, Zhuyang Feng, Qiuxia Liu, Jiandong Zhang, Xiang Wang, Dongxu Luo, Guangmao Yu, Desheng Wei, Ting Zhu","doi":"10.1016/j.yexcr.2026.115210","DOIUrl":"https://doi.org/10.1016/j.yexcr.2026.115210","url":null,"abstract":"<p><strong>Background: </strong>Lung squamous cell carcinoma (LUSC) is frequently characterized by aberrant activation of WNT/β-catenin signaling; however, the regulatory relationship between BIRC3 and BYSL in this pathway and in LUSC progression remains unclear. This study aimed to investigate the regulation of BYSL protein stability by BIRC3 and its association with malignant phenotypes in LUSC.</p><p><strong>Methods: </strong>The expression of BYSL and BIRC3 in LUSC was analyzed using The Cancer Genome Atlas (TCGA) database, and their protein expression levels were examined by Western blotting (WB) in five pairs of LUSC tumor tissues and matched adjacent non-tumor tissues. BYSL and BIRC3 were separately knocked down or overexpressed in NCI-H520 and NCI-H1703 cells, and cell proliferation, migration, and invasion were assessed using EdU, wound-healing, and Transwell assays. Co-immunoprecipitation, cycloheximide chase, MG132 treatment, and ubiquitination assays were performed to evaluate the interaction between BIRC3 and BYSL and the stability of BYSL protein. Cells were further subjected to combined shBYSL and oe-BIRC3 treatment or oe-BIRC3 plus the WNT/β-catenin pathway inhibitor MSAB, followed by analysis of pathway-related proteins and malignant cellular phenotypes. A nude mouse subcutaneous xenograft model was used for in vivo validation.</p><p><strong>Results: </strong>BYSL expression was elevated in LUSC tissues and cells, whereas BIRC3 expression was reduced in LUSC tissues. BYSL knockdown inhibited LUSC cell proliferation, migration, and invasion, whereas BYSL overexpression exerted opposite effects. BIRC3 interacted with BYSL; BIRC3 overexpression promoted BYSL ubiquitination and accelerated its proteasomal degradation, whereas BIRC3 knockdown reduced BYSL ubiquitination and enhanced BYSL protein stability. Both BIRC3 overexpression and BYSL knockdown were accompanied by decreased protein levels of WNT3A, β-catenin, TCF1, and c-Myc and attenuation of malignant cellular phenotypes, with more pronounced changes following combined intervention. In nude mice, BYSL knockdown inhibited xenograft tumor growth, and this inhibitory effect was further enhanced by combined BIRC3 overexpression.</p><p><strong>Conclusion: </strong>BIRC3 interacts with BYSL and promotes its ubiquitination and proteasomal degradation. BIRC3 overexpression and BYSL knockdown are associated with attenuation of WNT/β-catenin signaling and suppression of malignant phenotypes in LUSC, supporting a regulatory relationship among BIRC3, BYSL, and WNT/β-catenin signaling.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115210"},"PeriodicalIF":3.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAND1 Promotes Lung Cancer Tumorigenesis by Mitochondrial DNA Release mediated Neutrophil Infiltration.","authors":"Yiqiang Liu, Renchuan Liang, Yue Zhou, Junyang Chen, Zixuan Yuan, Hong Wu, Chuan Xu","doi":"10.1016/j.yexcr.2026.115196","DOIUrl":"https://doi.org/10.1016/j.yexcr.2026.115196","url":null,"abstract":"<p><strong>Background: </strong>CAND1, a conserved regulator of cullin-RING ubiquitin ligases, has been well characterized in protein homeostasis, but its functional role in lung adenocarcinoma (LUAD) remains largely unknown.</p><p><strong>Methods: </strong>Bioinformatic and clinical analyses assessed CAND1 expression and prognostic significance. Multiplex immunofluorescence and flow cytometry evaluated neutrophil infiltration and activation. Transwell assays and flow cytometry assessed neutrophil migration and NETosis. CAND1-modulated LUAD cells were used to examine mitochondrial remodeling, mtDNA release, cGAS-STING/NF-κB signaling, and chemokine expression, and Xenograft models to assess tumor growth and neutrophil involvement in vivo.</p><p><strong>Results: </strong>CAND1 is upregulated across multiple solid tumors, and its elevated expression is associated with poor prognosis in LUAD patients, as validated by public datasets and clinical cohort. CAND1 expression correlates with increased neutrophil infiltration and activation, which is further validated by co-culture experiments with isolated neutrophils and CAND1-overexpressing tumor cells. Mechanistically, CAND1 promotes mitophagy, leading to mtDNA release and sustained activation of the cGAS-STING/NF-κB signaling axis. STING knockdown markedly attenuated CAND1-associated neutrophil migration and reduced the expression of neutrophil-recruiting chemokines, including CCL5, CCL7, CXCL1, CXCL5, and CXCL8. In vivo, CAND1 overexpression accelerates xenograft tumor growth and enhances intratumoral neutrophil infiltration, while neutrophil depletion partially attenuates CAND1-associated tumor growth, supporting a functional contribution of neutrophils to CAND1-associated tumor progression.</p><p><strong>Conclusions: </strong>CAND1 links mitophagy to immune remodeling through cGAS-STING activation and subsequent chemokine-mediated neutrophil recruitment, establishing it as a key regulator of LUAD progression.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115196"},"PeriodicalIF":3.5,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nephroprotective Role of Berberine Against Chemotherapy-Induced Renal Toxicity: A Comprehensive Review.","authors":"Abolfazl Akbarzadeh, Mozhan Haji Ghaffari, Fatemeh Yarmohammadi","doi":"10.1016/j.yexcr.2026.115198","DOIUrl":"https://doi.org/10.1016/j.yexcr.2026.115198","url":null,"abstract":"<p><p>Chemotherapy-induced nephrotoxicity remains a major dose-limiting complication in cancer treatment. Accumulating evidence indicates that renal injury triggered by agents such as cisplatin, doxorubicin, methotrexate, and cyclophosphamide is primarily mediated by interconnected mechanisms including oxidative stress, mitochondrial dysfunction, inflammatory signaling, and apoptosis. Despite advances in supportive care, effective nephroprotective strategies remain limited. This review provides a comprehensive mechanistic synthesis of current preclinical evidence regarding the nephroprotective potential of berberine, a bioactive isoquinoline alkaloid. Rather than acting as a single-pathway antioxidant, berberine appears to exert pleiotropic cytoprotective effects through coordinated modulation of multiple signaling networks. These include activation of the Nrf2/Keap1 antioxidant defense system; regulation of autophagy and mitophagy via the AMPK/mTOR and PINK1/Parkin pathways; suppression of inflammatory cascades such as HMGB1/TLR4/RAGE, NF-κB, and MAPK signaling; and inhibition of mitochondrial-dependent apoptotic pathways through modulation of p53 and the Bax/Bcl-2 axis. By integrating these interconnected mechanisms, berberine restores redox homeostasis, preserves mitochondrial integrity, attenuates inflammatory amplification, and prevents tubular cell death. Collectively, the available evidence positions berberine as a promising multi-target adjunct candidate for mitigating chemotherapy-associated renal injury. However, clinical validation and pharmacokinetic optimization remain essential for translational application.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115198"},"PeriodicalIF":3.5,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant Human Follicle-Stimulating Hormone Injection versus Gonal-f® in Controlled Ovarian Stimulation for Assisted Reproductive Technology: A Multicenter, Randomized, Assessor-Blind, Active-Controlled Phase III Trial.","authors":"Haiyan Bai, Jingjing Li, Yang Wang, Bing Song, Xin Xu, Yongxin Sun, Qiuyun Niu, Caiyun Ma, Fan Xu, Jingjing Lin, Yunxia Cao, Jie Qiao","doi":"10.1016/j.yexcr.2026.115192","DOIUrl":"https://doi.org/10.1016/j.yexcr.2026.115192","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the equivalence in the number of oocytes retrieved, as well as to compare the safety and immunogenicity between the recombinant human follicle-stimulating hormone injection (LZ-B-01) and Gonal-f® for controlled ovarian stimulation (COS) in assisted reproductive technology (ART).</p><p><strong>Methods: </strong>This multicenter, randomized, assessor-blind, active-controlled phase III trial enrolled 379 Chinese women with infertility undergoing ART. Participants were randomized to receive LZ-B-01 (n=189) or Gonal-f® (n=190). Subcutaneous injections were initiated on menstrual cycle day 2-3, with a fixed starting dose based on age and weight for the first five days, followed by dose adjustments according to ovarian response, with a maximum stimulation duration of up to 20 days. The primary endpoint was the number of oocytes retrieved 36±2 hours after trigger, with an equivalence margin set at ±3.0 oocytes. An ANCOVA model was fitted with treatment group as fixed effect, stratification factors and baseline antral follicle count (<15 vs. ≥15) as covariates. Secondary endpoints included gonadotropin dose, stimulation duration, follicular development, hormone levels, embryological/pregnancy outcomes, immunogenicity, and safety.</p><p><strong>Results: </strong>Baseline characteristics were balanced between groups. The least squares mean number of oocytes retrieved was 13.0 (95% CI: 12.1-13.9) in the LZ-B-01 group and 12.3 (95% CI: 11.4-13.2) in the Gonal-f® group, with a mean difference (LZ-B-01 minus Gonal-f®) of 0.7 oocytes (95% CI: -0.4 to 1.9), which fell entirely within the pre-specified equivalence margin of ±3.0 oocytes, confirming efficacy equivalence. Secondary efficacy endpoints, including gonadotropin dose, stimulation duration, embryological parameters, and pregnancy outcomes, were comparable between the the two groups. No treatment-emergent anti-drug antibodies were detected in either group. The incidence of treatment-emergent adverse events was comparable between the LZ-B-01 and Gonal-f® groups (59.6% vs. 60.0%).</p><p><strong>Conclusion: </strong>LZ-B-01 demonstrated equivalent number of oocytes retrieved and a comparable safety profile to Gonal-f® for COS in ART, representing a suitable therapeutic alternative.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115192"},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OPTN-TRIP6-mediated F-actin mechanical support regulates phagophore closure to govern craniofacial skeletal development.","authors":"Zhenyi Lu, Hao Huang, Wanshu Lv, Jingjing Yan, Yumeng Shi, Jieli Ni, Yang Zhang, Rongyao Xu, Geng Wu, Shuyu Guo","doi":"10.1016/j.yexcr.2026.115195","DOIUrl":"10.1016/j.yexcr.2026.115195","url":null,"abstract":"<p><p>The development of craniofacial bones is highly dependent on the intramembranous ossification process driven by orofacial mesenchymal stem cells (OMSCs). Optineurin (OPTN), a traditional mitophagy receptor, promotes OMSC matrix mineralization by mediating the extracellular release of amorphous calcium phosphate (ACP) through the initiation of mitophagy via liquid-liquid phase separation. However, the dynamic mechanisms by which OPTN regulates mitochondrial engulfment remain elusive. In this work, we show that in both zebrafish and mouse models, Optn absence causes systemic bone loss and craniofacial abnormalities. Mechanistically, OPTN recruits thyroid receptor-interacting protein 6 (TRIP6) to the surface of damaged mitochondria, inducing local F-actin polymerization and remodeling, which relies on cytoskeletal mechanical forces to support the bending and closure of the phagophore. The depletion of OPTN or TRIP6 significantly impairs mitophagy flux, triggering a massive accumulation of dysfunctional mitochondria. Overall, this study elucidates that the OPTN-TRIP6-F-actin axis ensures autophagosome closure through cytoskeletal remodeling, revealing a novel paradigm in which cytoskeletal mechanical regulation maintains mitochondrial homeostasis to orchestrate craniofacial osteogenesis.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115195"},"PeriodicalIF":3.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction notice to “Tumor necrosis factor α stimulates endothelin-1 synthesis in rat hepatic stellate cells in hepatic wound healing through a novel IKK/JNK pathway” [Exp. Cell Res. 317 (2011) 1040-1048]","authors":"Shuxin Zhan,&nbsp;Don C. Rockey","doi":"10.1016/j.yexcr.2026.115130","DOIUrl":"10.1016/j.yexcr.2026.115130","url":null,"abstract":"","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"462 1","pages":"Article 115130"},"PeriodicalIF":3.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM117B promotes malignant progression of hepatocellular carcinoma by forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 pathway.","authors":"Zhaohong Wang, Jian Fang, Lijun Wu, Xinchang Zhang, Zihao Xu, Xiangyang Xue, Zhengfei Wang, Yunfeng Shan","doi":"10.1016/j.yexcr.2026.115151","DOIUrl":"10.1016/j.yexcr.2026.115151","url":null,"abstract":"<p><p>HCC (Hepatocellular carcinoma) is one of the malignant tumors with high morbidity and mortality worldwide. Its pathogenesis is complex and the efficacy of existing treatments is limited. Therefore, in-depth exploration of key regulatory molecules and their mechanisms is of great significance for the early diagnosis and targeted therapy of HCC. In this study, HCC cell lines Huh-7 and HepG2 were used as research models to systematically investigate the biological function and molecular regulatory mechanism of FAM117B (family with sequence similarity 117 member B) in HCC progression through gene knockdown and overexpression, cell functional assays, co-immunoprecipitation coupled with mass spectrometry, post-translational modification detection, transcriptome sequencing and nude mouse subcutaneous tumorigenesis assays. High FAM117B expression predicted poor prognosis and positively correlated with pathological grade; functionally, FAM117B exhibited robust oncogenic activity, where its knockdown suppressed proliferation, clonogenicity, invasion, and migration, and its overexpression enhanced these phenotypes. Mechanistic studies revealed that FAM117B directly physically interacted with NAT10 (N-acetyltransferase 10), an acetyltransferase, forming a bidirectional regulatory loop: on the one hand, FAM117B maintained the protein stability of NAT10 by inhibiting its K48-linked ubiquitination and subsequent proteasomal degradation; on the other hand, NAT10, as a key acetyltransferase, specifically mediated the acetylation of FAM117B at lysine 429, providing a molecular basis for the functional role of FAM117B. Transcriptome sequencing and molecular verification demonstrated that the FAM117B/NAT10 axis targeted and regulated JAK2 (Janus kinase 2) expression, activated the downstream JAK-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and thereby drove the malignant biological behaviors of HCC cells. In vivo, dual knockdown of FAM117B and NAT10 significantly reduced xenograft growth, decreased Ki67, and increased apoptosis; notably, NAT10 depletion abrogated the tumor-promoting effects of FAM117B overexpression. In conclusion, this study reveals the molecular mechanism by which FAM117B promotes HCC progression via forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 signaling pathway through acetylation modification, providing a novel potential target and theoretical basis for targeted therapy of HCC.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"115151"},"PeriodicalIF":3.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of CIRP in glioma Progression: Inhibition of ferroptosis via UBR5-Mediated ACSL4 degradation","authors":"Zhiyin Pang ,&nbsp;Xingwang Zu ,&nbsp;Ying Yang ,&nbsp;Pingping Yan ,&nbsp;Huicong Wang ,&nbsp;Junjie Liu ,&nbsp;Jinmin Hao","doi":"10.1016/j.yexcr.2026.114942","DOIUrl":"10.1016/j.yexcr.2026.114942","url":null,"abstract":"<div><div>Glioma represents the most aggressive form of primary brain tumor, characterized by restricted therapeutic strategies and unfavorable survival rates. Accumulating studies indicate that ferroptosis is critically involved in the advancement of glioma. Although cold-inducible RNA-binding protein (CIRP), an RNA chaperone protein, upregulated in various malignancies, has not been thoroughly investigated in glioma. This research revealed that CIRP is a significantly upregulated gene in glioma patients, with high expression correlating with worse prognosis. Through functional experiments, we demonstrated that CIRP enhances proliferative, migratory, and invasive capacities of glioma cells. Notably, we discovered that CIRP enhanced GBM cell resistance to ferroptosis, as evidenced by reduced intracellular iron levels, decreased lipid peroxidation, and elevated antioxidant capacity. Mechanistic studies revealed that CIRP facilitated the interaction between the E3 ubiquitin ligase UBR5 and ACSL4, leading to increased ubiquitination and subsequent proteasomal degradation of ACSL4. In summary, our findings indicate that CIRP advances glioma progression via inhibiting ferroptosis through the promotion of UBR5-mediated ACSL4 degradation.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"457 2","pages":"Article 114942"},"PeriodicalIF":3.5,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal modulation of cuproptosis and autophagy mediates nanographene-driven pulmonary fibrosis progression","authors":"Jiarui Xia ,&nbsp;Xiaolong Tang ,&nbsp;Huijie Shang ,&nbsp;Youliang Zhao ,&nbsp;Shuqi Li ,&nbsp;Ke Tang ,&nbsp;Yi Li ,&nbsp;Wenzhuo Wu ,&nbsp;Qun Xu ,&nbsp;Changfu Hao ,&nbsp;Wu Yao","doi":"10.1016/j.yexcr.2026.114927","DOIUrl":"10.1016/j.yexcr.2026.114927","url":null,"abstract":"<div><div>Graphene nanoparticles are increasingly used in materials manufacturing, pollutant treatment, energy storage, and electronic devices, and the potential risk of occupational and environmental exposure is a concern. The mechanisms of lung fibrosis induced by nano-graphene with different properties are complex. In addition, multiple modes of programmed cell death (PCD) occur during lung fibrosis, and whether cuproptosis and autophagy exert regulatory effects during the progression of lung fibrosis induced by nano-graphene remains undocumented. In this study, we constructed mouse models with varying doses of graphene and exposure durations. We observed the dynamics of pathological changes in lung histology and the time-series expression of biomarkers. We discovered that graphene could deposit in lung tissue, leading to the pathological manifestations of pulmonary fibrosis; this was coincident with elevated copper ion concentration, cellular cuproptosis, and excessive autophagy. In short, our results may contribute to further elucidation of the potential respiratory toxic effects and mechanisms of graphene, and to the early development of targeted preventive and control measures by providing new ideas and reference points.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"457 1","pages":"Article 114927"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin-like growth factor-1 enhances β-amyloid protein clearance in HMC3 microglia via low-density lipoprotein receptor-related protein 1-mediated pathway","authors":"Hongsong Guo,&nbsp;Xiaoqian Peng,&nbsp;Xiao Zhang,&nbsp;John Bosco Ruganzu,&nbsp;Xiangyuan Wu,&nbsp;Mingtao Zhao,&nbsp;Pengbo Yang,&nbsp;Shengfeng Ji,&nbsp;Weina Yang","doi":"10.1016/j.yexcr.2026.114920","DOIUrl":"10.1016/j.yexcr.2026.114920","url":null,"abstract":"<div><div>β-amyloid protein (Aβ) deposition occurs years before cognitive symptoms appear and is considered one of the main causes underlying the pathogenic events that occur in Alzheimer's disease (AD). Mounting evidence suggests that the imbalance of Aβ production and clearance leads to the accumulation of Aβ and the subsequent formation of toxic Aβ aggregates. Aβ is internalized by microglia and transported to lysosomes for degradation, which is one of the main ways by which Aβ may be cleared from the brain. Insulin-like growth factor-1 (IGF-1) promotes clearance of Aβ in the brain by enhancing Aβ carrier proteins. Our previous study demonstrated that low-density lipoprotein receptor-related protein 1 (LRP1) mediates the internalization of Aβ_1-42 and lysosomal trafficking in primary cortical neurons. However, whether IGF-1 enhances the clearance of Aβ in microglia through the LRP1-mediated pathway and its underlying mechanisms is incompletely understood. Here, we reported that knockdown of LRP1 expression significantly decreased the internalization of Aβ_1-42 in HMC3 cells. Furthermore, pretreatment with IGF-1 significantly increased intracellular Aβ_1-42, indicating IGF-1 enhances HMC3 cells uptake of extracellular Aβ_1-42. Interestingly, the intracellular Aβ_1-42 in LRP1-knockdown HMC3 cells was reduced after preincubation with IGF-1. Thus, it was indicated that LRP1 is essential for IGF-1-enhanced internalization of Aβ_1-42 in HMC3 cells. Moreover, IGF-1 significantly inhibited the downregulation of PI3K, phospho-PI3K, Akt, and phospho-Akt induced by Aβ_1-42. Importantly, treatment with LY294002, a PI3K inhibitor, significantly reduced the intracellular Aβ_1-42 levels and decreased the expression of LRP1. These findings indicated that IGF-1 enhances the internalization of Aβ in a LRP1-dependent manner by activating the PI3K/Akt signaling pathway. Finally, we identified that IGF-1 promotes lysosomal proteolysis of Aβ_1-42 by increasing cathepsin B (CTSB) and cathepsin D (CTSD) expression. Consequently, these results demonstrated that IGF-1 promotes the internalization and lysosomal degradation of Aβ by microglia, which is an effective approach to lowering brain Aβ levels, and it might be a promising therapeutic target for AD.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"457 1","pages":"Article 114920"},"PeriodicalIF":3.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}