Journal of Translational Internal Medicine
·
2023
·Vol. 11
·期 3
·294-308
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IF 4.9
Naiquan Liu,Dongyang Li,Dajun Liu,Ying Liu,Jing Lei
Background
Fos-related antigen 2 ( FOSL2 ) plays a facilitative role in fibrotic disease; however, its role in renal fibrosis remains unclear. This study aimed to clarify the role and underlying mechanisms of FOSL2 in renal fibrosis.
Methods
Upregulated genes in unilateral ureteral obstruction (UUO)-injured kidneys were screened in Gene Expression Omnibus (GEO) databases, and overlapping genes were identified using Venn diagram software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for these genes. The UUO-induced mouse model and transforming growth factor-β1 (TGF-β1)-induced cell model were used for the in vivo and in vitro studies.
Results
A total of 43 commonly upregulated genes were identified. GO and KEGG pathway analyses indicated that FOSL2 may be involved in fibrosis. Furthermore, FOSL2 was confirmed to be upregulated in UUO-injured kidneys and TGF-β1–induced cells. Knockdown of FOSL2 ameliorated interstitial fibrosis, extracellular matrix deposition, and epithelial-mesenchymal transition via the downregulation of fibronectin, α-smooth muscle actin (α-SMA), collagen type I ( Col1a1 and Col1a2 ), and Col5a1 and upregulation of E-cadherin . Bioinformatics analysis revealed that serum/glucocorticoid regulated kinase 1 ( SGK1 ) may be regulated by FOSL2 and involved in renal fibrosis. Further experiments confirmed that TGF-β1 enhanced SGK1 expression and transcription, which were reversed by FOSL2 silencing. Moreover, FOSL2 was bound to the SGK1 promoter, and SGK1 overexpression reversed the effects of FOSL2 silencing in TGF-β1–induced cells.
Conclusion
FOSL2 plays an essential role in promoting renal fibrosis in an SGK1 -dependent manner, and targeting the FOSL2 / SGK1 signaling axis may offer a potential strategy for the treatment of renal fibrosis.
研究领域:
肾病学
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分子生物学
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细胞生物学
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病理学
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EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Yanhua Jin,Huan Wang,Yu Xin,Yanning Zhang
Mitochondrial dysfunction is a pivotal factor in the onset of podocyte damage, which is a central component in the pathogenesis of nephrotic syndrome (NS). However, the precise mechanisms underlying the changes in podocyte mitochondria remain elusive. Our study aims to clarify the potential mechanisms involved in the role of F-box protein 11 (Fbxo11) in NS, specifically concentrating on its impact on mitochondrial function. A mouse model was established by tail vein injection of adriamycin (ADR, 10 mg/kg) and was infected with lentivirus overexpressing Fbxo11. Mouse podocytes (MPC-5) were infected with lenti-Fbxo11-OE, followed by treatment with 0.4 μg/mL of ADR. We identified the decreased expression of Fbxo11 in mouse kidney tissues and MPC-5 cells induced by ADR. Lenti-Fbxo11-OE intervention relieved ADR-induced glomerular lesion, podocyte injury, and mitochondrial dysfunction. In vitro, overexpression of Fbxo11 in mouse podocytes improved mitochondrial function and reduced podocyte damage, thereby inhibiting podocyte apoptosis. Mechanistically, Fbxo11 decreased the protein expression of Fosl2 through ubiquitin-dependent proteasomal degradation. Rescue experiments revealed that overexpression of Fosl2 abolished the protective effects of Fbxo11 overexpression on mitochondrial damage and podocyte injury. Importantly, the regulatory effects of the Fbxo11/Fosl2 axis were reversed when treated with the mitochondrial fission inhibitor mdivi-1. Taken together, our results demonstrated that Fbxo11-mediated ubiquitin degradation of Fosl2 is critical for maintaining mitochondrial function and preventing podocyte injury during NS.
研究领域:
肾病学
·
分子生物学
·
细胞生物学
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Advanced Science
·
2025
·
IF 14.1
Xuming Song,Zehao Pan,Yi Zhang,Wenmin Yang,Te Zhang,Hui Wang,Yuzhong Chen,Xinnian Yu,Hanlin Ding,Rutao Li,Pengfei Ge,Lin Xu,Gaochao Dong,Feng Jiang
Current understanding of micropapillary (MP)-subtype lung adenocarcinoma (LUAD) remains confined to biological activities and genomic landscapes. Unraveling the major regulatory programs underlying MP patterned malignancy offers opportunities to identify more feasible therapeutic targets for patients with MP LUAD. This study shows that patients with MP subtype LUAD have aberrant activation of the MYC pathway compared to patients with other subtypes. In vitro and xenograft mouse model studies reveal that MP pattern in malignancy cannot be solely due to aberrant MYC expression but requires the involvement of M2-like macrophages. Excessively expressed MYC leads to the accumulation of M2-like macrophages from the bone marrow, which secretes TGFβ, to induce the expression of FOSL2 in tumor cells, thereby remodeling chromatin accessibility at promoter regions of MP-pattern genes to promote the MYC-mediated de novo transcriptional regulation of these genes. Additionally, the MP-pattern in malignancy can be effectively alleviated by disrupting the TGFβ-FOSL2 axis. These findings reveal new functions for the M2-like macrophage-TGFβ-FOSL2 axis in MYC-overexpressing MP-subtype LUAD, identifying targetable vulnerabilities in this pathway.
研究领域:
肿瘤学
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分子生物学
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免疫学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Wangshi Li,Meiling Sun,Binyu Yao,Xinyu Li,Ting Qiu,Xingzhi Lv,Yue Wu,Xingxing Du,Fukai Liu,Ruolin Xiu,Yanhong Zhao,Shengjin Fan,Keyang Luo,Huitao Fan
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor clinical outcomes and high relapse rates, driven largely by intrinsic or acquired chemoresistance. Despite advances, the standard "7 + 3″ chemotherapy backbone offers limited long-term survival, underscoring the urgent need for novel molecular targets to overcome therapeutic bottlenecks. While the AP-1 transcription factor FOSL2 is implicated in solid tumors, its role in AML remains unexplored. Here, we identify and validate FOSL2 as a critical oncogenic driver in AML. Comprehensive bioinformatic analysis across multiple independent patient cohorts reveals that its aberrant overexpression is a key feature and robust biomarker, correlating significantly with adverse clinical outcomes. Functional studies using shRNA-mediated silencing demonstrated that FOSL2 is indispensable for leukemic cell survival and proliferation. Its genetic depletion profoundly abrogated clonogenic potential, induced G0/G1 cell-cycle arrest and apoptosis, and promoted myeloid differentiation in vitro. In a xenograft mouse model, FOSL2 knockdown markedly suppressed leukemic tumor burden and significantly extended overall survival. Mechanistically, transcriptomic profiling revealed that FOSL2 depletion upregulates the E3 ubiquitin ligase HRD1 suggesting that FOSL2 depletion may hyperactivate the endoplasmic reticulum-associated degradation (ERAD) pathway. This uncontrolled ERAD activity dismantles cellular proteostasis, culminating in heightened ER stress and significant DNA damage, as evidenced by comet assays. Consequently, this FOSL2-deficient state profoundly sensitizes AML cells to conventional chemotherapies, including doxorubicin and cytarabine, as well as ER stress-inducing agents. Collectively, these findings establish that FOSL2 orchestrates a key proteostatic vulnerability. Targeting the FOSL2-ERAD axis represents a compelling therapeutic strategy to dismantle chemoresistance and improve patient outcomes in AML.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Zexin Li,Xiao Wang,Yuanyuan Cui,Rui Wei,Yixin Wang,Yi Liu,Lifang Li,Jiasai Li,Liangbin Li,Keqiang Zuo
Macrophage-mediated inflammatory response is a critical pathogenic component in hepatic ischemia/reperfusion injury (HIRI) development. Although FOS-like antigen 2 (FOSL2) plays a pivotal role in regulating macrophage polarization, its role and potential mechanisms in HIRI remain unclear. The findings demonstrated that FOSL2 exhibited elevated expression levels in both the liver tissues and macrophages of the liver tissues in IR rats. Knockdown of FOSL2 significantly alleviated HIRI-induced liver injury, accompanied by the suppression of hepatic tissue apoptosis and oxidative stress. Furthermore, FOSL2 knockdown led to a reduction in the pro-inflammatory M1 phenotype and an increase in the anti-inflammatory M2 phenotype of Kupffer cells (KCs). Concomitantly, FOSL2 expression was markedly upregulated in KCs following lipopolysaccharide (LPS) stimulation, and FOSL2 silencing potently promoted the phenotypic switch of KCs from the pro-inflammatory M1 to the anti-inflammatory M2 state. Additionally, knockdown of FOSL2 in KCs attenuated KC-induced hepatocyte apoptosis and oxidative stress. Transcriptomic analysis conducted on liver tissues from HIRI rats with or without FOSL2 knockdown identified a significant downregulation of activating transcription factor 4 (ATF4), with a log2 fold change of −1.51 and a p-value < 0.05. Mechanistically, FOSL2 bound to the promoter region of ATF4 to drive its transcription, and ATF4 overexpression abrogated the phenotypic and functional effects elicited by FOSL2 silencing. Collectively, our findings illustrate that FOSL2 knockdown exerts a protective role against IR-induced hepatic stress, highlighting the importance of FOSL2 as a potential therapeutic target for HIRI.
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