Ask about this productRelated genes to: FBXL4 antibody
- Gene:
- FBXL4 NIH gene
- Name:
- F-box and leucine rich repeat protein 4
- Previous symbol:
- -
- Synonyms:
- FBL4, FBL5
- Chromosome:
- 6q16.1-q16.2
- Locus Type:
- gene with protein product
- Date approved:
- 2000-09-27
- Date modifiied:
- 2018-02-13
Related products to: FBXL4 antibody
Related articles to: FBXL4 antibody
- In multiple myeloma (MM), resistance to B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) treatment continues to limit therapeutic benefit, whereas the tumor-intrinsic factors governing sensitivity to CAR-T remain poorly understood. Here, integrating public single-cell RNA-seq data with transcriptomic profiling of MM cells before and after CAR-T exposure, we identified the mitochondrial protein PPTC7 as a key modulator linking tumor mitophagy to innate immune activation and CAR-T efficacy. Mechanistically, PPTC7 acted as a negative regulator of tumor-intrinsic mitophagy by promoting SCF^FBXL4-dependent ubiquitination and proteasomal degradation of the mitophagy receptors BNIP3 and NIX, thereby suppressing mitophagic flux. Consistent with this, PPTC7 overexpression inhibited mitophagy, caused mitochondrial dysfunction, and increased cytosolic leakage of mitochondrial DNA (mtDNA), whereas PPTC7 knockdown stabilized BNIP3/NIX, enhanced mitophagy, and reduced cytosolic mtDNA. The accumulated cytosolic mtDNA consequent to mitophagy suppression activated the cGAS/STING pathway, induced a senescence-associated secretory phenotype, and remodeled the inflammatory tumor microenvironment. Functionally, PPTC7-mediated mitophagy repression markedly enhanced CAR-T cytotoxicity in vitro and promoted CAR-T infiltration and tumor control in vivo. Rescue experiments further supported this axis: restoring mitophagy via NIX attenuated mtDNA leakage and dampened cGAS/STING signaling and CAR-T activity, whereas re-activating cGAS reinstated inflammatory signaling and CAR-T effector function. Collectively, our findings define a tumor-intrinsic PPTC7-BNIP3/NIX-mtDNA-cGAS/STING circuit in which suppression of mitophagy increases tumor immunogenicity and sensitizes MM to CAR-T therapy, highlighting PPTC7 as a potential immune-sensitizing target to overcome CAR-T resistance. - Source: PubMed
Publication date: 2026/04/18
Yu KuaiXiong XinxinLu BoWang YaqunSun TiantianXie MeiXu XiaojunSong YuanbinXiao Wei - Steroid-induced osteonecrosis of the femoral head (SONFH) is a major cause of disability among young and middle-aged adults. However, current diagnosis relies primarily on imaging findings and clinical manifestations, as stable and reliable molecular biomarkers for adjunctive diagnosis and risk stratification remain lacking, thereby hindering timely and effective intervention. Aberrant lactate metabolism is thought to contribute to the onset and progression of various inflammatory diseases by reshaping the inflammatory microenvironment and reprogramming immune responses. However, its role and regulatory mechanisms in SONFH remain understudied. In this study, we analyzed transcriptomic data from SONFH patients in the GEO database, integrating differential expression analysis with weighted gene co-expression network analysis (WGCNA) to identify SONFH-associated genes and co-expression modules. Cross-screening with lactate-related genes (LRGs) curated in the MSigDB database yielded a set of LRGs closely associated with SONFH. Unsupervised consensus clustering was then applied to stratify patients into molecular subtypes, and a machine-learning-based diagnostic model was constructed. In parallel, gene set variation analysis (GSVA) and CIBERSORT were used to characterize metabolic states and immune cell infiltration across subtypes, with a focus on LRGs implicated in metabolic reprogramming and immune dysregulation. Finally, bone marrow-derived mesenchymal stem cells (BMSCs) were collected from Sprague-Dawley rats and humans, along with peripheral blood from patients, and in vitro experiments confirmed significant downregulation of BPGM, FBXL4, and RHAG in SONFH, genes closely linked to bone metabolic imbalance and immune microenvironment remodeling. Collectively, these findings systematically elucidate the potential molecular regulatory role of LRGs in SONFH and provide a theoretical basis for its auxiliary diagnosis and the development of targeted therapeutic strategies. - Source: PubMed
Wang ZehuaDong ShuhangXu KaigeTang XinyuGuo SijiaJiang YapingZhang YingzeLi Tao - Mitochondrial DNA depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder presenting in early infancy with encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Patient-derived cells typically exhibit impaired mitochondrial oxidative phosphorylation and a marked reduction in mitochondrial DNA (mtDNA) copy number. - Source: PubMed
Publication date: 2026/02/02
D'Amato GabrieleGentile MattiaCarella RossellaGiannini AntonioFaienza Maria FeliciaTummolo Albina - Pathological cardiac hypertrophy is characterized by profound disruptions in protein turnover, a hallmark of maladaptive cardiac remodeling. This study aimed to elucidate the role and underlying molecular mechanisms of an FBP, F-box and leucine-rich repeat protein 4 (FBXL4), in pathological cardiac hypertrophy. Transcriptomic analysis of murine heart failure and human dilated cardiomyopathy samples revealed consistent downregulation of FBXL4. Similarly, FBXL4 expression was reduced in failing human hearts, hypertrophic mouse hearts, and angiotensin II (Ang II)-treated neonatal mouse cardiomyocytes (NMCMs). Inducible ablation of FBXL4 in cardiomyocytes resulted in HF with reduced cardiac function, an enlarged heart chamber, increased fibrosis, and myofibrillar disorganization and sarcomere remodeling. Conversely, cardiac-specific overexpression of FBXL4 attenuated pressure overload-induced hypertrophy. Mechanistically, FBXL4 interacts with PFN1 and promotes its K48-linked ubiquitination at lysine 70, leading to its proteasomal degradation and the preservation of sarcomeric integrity. Restoration of FBXL4 expression via AAV9 delivery ameliorated cardiac hypertrophy and dysfunction in FBXL4-iCKO mice, while AAV9-mediated PFN1 knockdown or pharmacological inhibition partially reversed these phenotypes. Furthermore, the transcription factor SP1 was found to repress FBXL4 expression during hypertrophy. FBXL4 deficiency also induced hypertrophic features in hiPSC-derived cardiomyocytes. Together, these findings establish FBXL4 as a key regulator of sarcomere integrity and cardiac function through ubiquitin-mediated degradation of PFN1. - Source: PubMed
Publication date: 2026/01/27
Li XingdaHe XueqiHao XinyuanZhang YuZhao XinWang ShuangWang ZhenruDu HaonanLi HongdaYi LianDu ZhiminDu Weijie - Cepharanthine (Cep), a natural alkaloid from Stephania (Menispermaceae), exhibits broad-spectrum anti-cancer activity. In the present study, Cep was found to induce ferroptosis and mitophagy, for which the relationship and upstream targets remain unelucidated. Herein, the role of Cep in the induction of mitophagy was deeply investigated. Cep showed robust anti-lung cancer effects, as confirmed by decreased cell viability, elevated apoptosis, suppressed colony formation and inhibited growth of tumor grafts in Lewis cell-bearing mice. RNA-sequencing analysis revealed that Cep treatment significantly enriched differentially expressed genes (DEGs) in mitophagy and ferroptosis pathways, which were demonstrated in in vitro and in vivo experiments as well. In-depth investigations showed that inhibition of autophagy abolished Cep-mediated ferroptosis, but not vice versa. Moreover, genetic knockdown of BNIP3 dampened the mitophagy and ferroptosis of lung cancer cells induced by Cep. Additional data confirmed that Cep could bind to and thereby inhibit FBXL4, which attenuated the ubiquitination of BNIP3. FBXL4-mediated BNIP3 activation promoted the recruitment of LC3 to mitochondria and autophagic flux in the presence of Cep. Collectively, Our study elucidates a complete mechanistic pathway wherein Cep activates BNIP3-mediated mitophagy by inhibiting FBXL4, ultimately driving ferroptosis and offering a new therapeutic avenue for lung cancer. - Source: PubMed
Publication date: 2025/10/31
Li Liu-GenXu Yong-HongHan NingLeng FanHu JunXu Hua-ZhenHuang HongyaoLi Tong-FeiChen Xiao