Affinage

FNDC4

Fibronectin type III domain-containing protein 4 · UniProt Q9H6D8

Length
234 aa
Mass
25.2 kDa
Annotated
2026-06-09
21 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FNDC4 is a secreted fibronectin type III domain-containing protein that functions as a pleiotropic endocrine/paracrine factor coordinating metabolic, inflammatory, and tissue-protective responses across multiple organs (PMID:12384288, PMID:34016966). Originally identified as a brain- and liver-expressed member of a new FNIII-repeat gene family (PMID:12384288), its soluble form binds with high affinity to the orphan adhesion GPCR GPR116 in white adipose tissue to promote insulin signaling and glucose uptake, with the liver serving as the primary source of circulating sFNDC4 and hepatic FNDC4 loss driving prediabetes (PMID:34016966). In adipocytes FNDC4 additionally suppresses lipogenesis and drives browning and mitochondrial biogenesis (PMID:32407726). A recurrent anti-inflammatory and pro-survival theme runs through its actions on innate immune cells: FNDC4 binds macrophages and monocytes to suppress NF-κB activity, reduce proinflammatory chemokine expression, and enhance cell survival (PMID:27066907, PMID:41819760), and it inhibits RANKL-induced osteoclastogenesis via NF-κB suppression and CXCL10 downregulation (PMID:29977911). In parenchymal tissues it acts as a survival and metabolic-protective factor: it stabilizes HIF1α to protect cardiomyocytes during ischemia/reperfusion and drives paracrine FGF1-mediated angiogenesis (PMID:39516487), engages AMPKα-dependent signaling to limit hepatocyte cell death and improve mitochondrial function (PMID:39173437), and signals through AMPK/YAP to restrain hepatic stellate cell fibrogenesis (PMID:41802610). FNDC4 also regulates the balance of glutamatergic versus GABAergic neurons during human cortical neurogenesis (PMID:41505223), and in several cancers it modulates CCAR1/β-catenin, PI3K/Akt, and macrophage M2 polarization pathways (PMID:41066593, PMID:34418326).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established FNDC4 as a distinct fibronectin type III repeat-containing gene with a defined developmental and adult tissue expression pattern, providing the foundational identification on which all later functional work rests.

    Evidence Molecular cloning and cross-tissue expression profiling

    PMID:12384288

    Open questions at the time
    • No protein function or receptor identified
    • No mechanism linking expression pattern to activity
  2. 2016 High

    Defined FNDC4 as a direct anti-inflammatory regulator of innate immunity by showing selective binding to macrophages/monocytes and suppression of proinflammatory output, addressing whether the secreted protein has a cell-targeted function.

    Evidence Recombinant protein binding, in vitro macrophage assays, and Fndc4 knockout/rescue in a mouse colitis model

    PMID:27066907

    Open questions at the time
    • Macrophage receptor not identified
    • Molecular basis of cell-type-selective binding unresolved
  3. 2020 Medium

    Showed FNDC4 acts on adipocytes to suppress lipogenesis and promote browning and mitochondrial biogenesis, extending its role into metabolic tissue programming.

    Evidence Gain- and loss-of-function in human visceral adipocytes with lipid, gene expression, and mitochondrial DNA readouts

    PMID:32407726

    Open questions at the time
    • Receptor dependence not directly tested in this system
    • In vivo relevance not established here
  4. 2021 High

    Identified the orphan adhesion GPCR GPR116 as a high-affinity receptor for soluble FNDC4 and established a hepatic-FNDC4-to-adipose axis controlling systemic glucose homeostasis, answering what receptor transduces its metabolic effects.

    Evidence Receptor identification, direct binding affinity assays, liver- and adipocyte-specific genetic models, and receptor-dependent glucose tolerance rescue in prediabetic mice

    PMID:34016966

    Open questions at the time
    • Downstream GPR116 signaling steps not fully mapped
    • Whether GPR116 mediates non-adipose FNDC4 effects unknown
  5. 2018 Medium

    Linked FNDC4's anti-inflammatory NF-κB suppression to skeletal biology by showing it inhibits osteoclastogenesis through CXCL10 downregulation, with functional rescue establishing pathway dependence.

    Evidence TRAP/resorption assays, NF-κB luciferase reporter, and CXCL10 rescue in BMM and RAW264.7 cells

    PMID:29977911

    Open questions at the time
    • Receptor mediating osteoclast effects not identified
    • In vivo bone phenotype not tested
  6. 2024 High

    Defined a cardioprotective mechanism in which FNDC4 stabilizes HIF1α and drives paracrine FGF1 secretion, distinguishing cardiomyocyte survival from indirect angiogenesis.

    Evidence Cardiac-specific overexpression/knockdown mice, I/R model, HIF1α degradation and FGF1 secretion assays

    PMID:39516487

    Open questions at the time
    • Receptor controlling cardiac HIF1α stabilization not identified
    • Mechanism of HIF1α proteasomal regulation not molecularly resolved
  7. 2024 Medium

    Established AMPKα as a required mediator of FNDC4-driven hepatocyte survival and mitochondrial maintenance under inflammatory stress.

    Evidence Knockdown/recombinant treatment in HepG2 with cell-death, mitochondrial DNA, OXPHOS readouts and AMPKα epistasis

    PMID:39173437

    Open questions at the time
    • Receptor coupling FNDC4 to AMPKα unknown
    • In vivo hepatocyte relevance not tested
  8. 2023 Medium

    Extended FNDC4's anti-inflammatory action to rheumatoid arthritis synoviocytes via CCL2/ERK suppression, with rescue confirming pathway dependence.

    Evidence FNDC4 overexpression in RA fibroblast-like synoviocytes with CCL2 and ERK-activator rescue

    PMID:38181585

    Open questions at the time
    • Receptor not identified
    • Mechanism linking FNDC4 to CCL2 suppression unresolved
  9. 2025 Medium

    Showed FNDC4 protects aging hearts through AMPKα/PPARα signaling against lipotoxicity, reinforcing AMPK as a recurrent downstream node.

    Evidence Cardiac-specific overexpression/knockdown mice with transcriptomics and metabolomics

    PMID:40464727

    Open questions at the time
    • Receptor upstream of cardiac AMPKα/PPARα unknown
    • Single-lab pathway attribution
  10. 2026 Medium

    Demonstrated AMPK/YAP-dependent anti-fibrotic action of FNDC4 on hepatic stellate cells, integrating its metabolic and fibrogenic regulation in liver.

    Evidence Recombinant FNDC4 treatment of LX-2 HSCs with collagen, ROS, YAP, and AMPKα readouts

    PMID:41802610

    Open questions at the time
    • Receptor not identified
    • In vivo fibrosis model not tested here
  11. 2026 Medium

    Revealed unexpected intracellular/nuclear roles for FNDC4 in pancreatic cancer through CCAR1/β-catenin stabilization and tumor-immune M2 polarization, broadening its functional repertoire beyond secreted signaling.

    Evidence FNDC4 knockdown in PDAC models, CCAR1/β-catenin and macrophage/T-cell analyses, immunofluorescence, and immunocompetent in vivo models

    PMID:41066593

    Open questions at the time
    • Nuclear localization based on single method
    • BHLHE40 transcriptional control not independently confirmed
    • Reconciliation of nuclear versus secreted function unresolved
  12. 2026 Medium

    Established a role for FNDC4 in human cortical neurogenesis by showing knockout shifts glutamatergic/GABAergic neuron proportions and electrical activity.

    Evidence CRISPR/Cas9 knockout in iPSC-derived forebrain organoids with single-nucleus RNA-seq and electrophysiology

    PMID:41505223

    Open questions at the time
    • Proposed neural cell-surface interaction mechanism not resolved
    • Receptor/partner in neurons unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying receptor logic and signaling steps that allow one secreted protein to produce anti-inflammatory, metabolic, cardioprotective, anti-fibrotic, neurodevelopmental, and oncogenic outputs remain unresolved, as does whether GPR116 mediates effects beyond adipose tissue and how a secreted protein achieves nuclear function.
  • No receptor identified for most non-adipose contexts
  • Mechanism reconciling secreted versus nuclear roles unknown
  • No structural model of FNDC4-receptor engagement

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
GPR116

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 FNDC4 (Frcp1) was cloned and identified as a member of a new fibronectin type III (FNIII) repeat-containing gene family; it is primarily expressed in the brain during embryonic development and strongly expressed in the liver in adult tissues. Molecular cloning and expression analysis Gene Medium 12384288
2016 FNDC4 binds specifically to macrophages and monocytes (but not other immune cell types); treatment of bone marrow-derived macrophages with recombinant FNDC4 reduces phagocytosis, increases cell survival, and reduces proinflammatory chemokine expression, placing FNDC4 as a direct anti-inflammatory regulator of macrophage activity. Recombinant protein binding assays to immune cell types, in vitro macrophage treatment, phagocytosis assays, chemokine expression profiling, mouse colitis model with Fndc4 knockout and recombinant FNDC4 administration Nature communications High 27066907
2020 FNDC4 reduces lipogenesis and stimulates browning of human visceral adipocytes, upregulating UCP-1, PRDM16, TMEM26, CD137, mitochondrial DNA content, and mitochondrial biogenesis factors (TFAM, NRF1, NRF2); FNDC4 knockdown in adipocytes increases lipogenesis and reduces brown/beige fat markers. The putative receptor GPR116 is expressed in visceral adipose tissue. Recombinant FNDC4 treatment of human visceral adipocytes, FNDC4 knockdown (siRNA), lipid accumulation assays, gene expression (RT-qPCR/western blot), mitochondrial DNA quantification Metabolism: clinical and experimental Medium 32407726
2021 Soluble FNDC4 (sFNDC4) binds directly and with high affinity to the orphan adhesion GPCR GPR116 in white adipose tissue; this binding promotes insulin signaling and insulin-mediated glucose uptake in white adipocytes; the liver is the primary source of circulating sFNDC4; lowering hepatic FNDC4 causes prediabetes in mice; FcsFNDC4 supplementation improves glucose tolerance in prediabetic mice in a GPR116-dependent manner. Receptor identification (GPR116), direct binding affinity assays, white adipocyte insulin signaling assays, liver-specific and adipocyte-specific genetic models, glucose tolerance tests in prediabetic mice Nature communications High 34016966
2018 FNDC4 inhibits RANKL-induced osteoclastogenesis and mature osteoclast resorptive function in a dose-dependent manner by suppressing NF-κB transcriptional activity; FNDC4 treatment drastically downregulates CXCL10, and supplementation of CXCL10 partially rescues FNDC4-induced inhibition of osteoclast formation. TRAP staining, bone resorption pit assay, NF-κB luciferase reporter assay, western blotting, recombinant FNDC4 treatment of BMMs and RAW264.7 cells, CXCL10 rescue experiment BioMed research international Medium 29977911
2021 The extracellular domain of FNDC4 acts as a secreted factor to promote Akt phosphorylation and stimulate invasion and migration of hepatocellular carcinoma cells via the PI3K/Akt signalling pathway. Recombinant extracellular FNDC4 domain treatment of HCC cells, western blot for p-Akt, migration/invasion assays Cancer medicine Low 34418326
2024 In the heart, cardiac and plasma FNDC4 levels are elevated during ischemia/reperfusion injury in a HIF1α-dependent manner; FNDC4 regulates proteasomal degradation of HIF1α to promote cardiomyocyte survival; FNDC4 does not directly stimulate angiogenesis of endothelial cells but increases expression and secretion of FGF1 from cardiomyocytes to enhance angiogenesis in a paracrine manner; cardiac-specific FNDC4 overexpression is protective while knockdown worsens I/R injury. Cardiac-specific overexpression and knockdown mouse models, I/R injury model, HIF1α proteasomal degradation assay, FGF1 secretion measurement, endothelial cell angiogenesis assay, recombinant FNDC4 administration Nature communications High 39516487
2024 FNDC4 acts as a hepatocyte survival factor: it inhibits NLRP3 inflammasome-induced pyroptosis, apoptosis, and necroptosis in TNF-α-stimulated hepatocytes; it improves TNF-α-induced mitochondrial dysfunction by enhancing mitochondrial DNA copy number and OXPHOS complex subunits; AMPKα is required for FNDC4-mediated inhibition of cell death and increase in mitochondrial DNA content. FNDC4 knockdown and recombinant FNDC4 treatment in HepG2 hepatocytes, cell death assays (pyroptosis/apoptosis/necroptosis), mitochondrial DNA quantification, OXPHOS complex western blot, AMPKα inhibition/knockdown epistasis Clinical nutrition (Edinburgh, Scotland) Medium 39173437
2023 FNDC4 overexpression in RA fibroblast-like synoviocytes inhibits cell proliferation, invasion, migration, and inflammatory factor release while promoting apoptosis; this is mediated by suppression of the CCL2/ERK signaling pathway; overexpression of CCL2 or activation of ERK with tBHQ rescues the FNDC4-induced effects. FNDC4 overexpression plasmid transfection, proliferation/apoptosis/migration/invasion assays, cytokine expression, western blot for ERK pathway, CCL2 overexpression and ERK activator rescue experiment Tissue & cell Medium 38181585
2025 FNDC4 activates the AMPKα/PPARα signaling pathway to improve mitochondrial dysfunction and lipotoxicity in aging hearts; cardiac-specific FNDC4 overexpression alleviates while knockdown worsens aging-related cardiac remodeling and dysfunction. Cardiac-specific overexpression and knockdown mouse models, transcriptome analysis, untargeted metabolomics, AMPKα/PPARα pathway analysis JACC. Basic to translational science Medium 40464727
2026 In pancreatic ductal adenocarcinoma, FNDC4 enhances CCAR1 protein stability, thereby sustaining CCAR1/β-catenin signaling to support invasion and colony formation; FNDC4 also drives M2 macrophage polarization to promote immune evasion; loss of FNDC4 shifts macrophage polarization toward antitumor M1 and increases CD4+/CD8+ T-cell infiltration; FNDC4 unexpectedly localizes to the nucleus; BHLHE40 directly activates FNDC4 transcription; CCL5 is a downstream effector mediating immune effects of FNDC4 inhibition. FNDC4 knockdown in PDAC models, CCAR1/β-catenin western blot, macrophage polarization flow cytometry, T-cell infiltration analysis, immunofluorescence for nuclear localization, transcriptomic analysis, in vivo xenograft and immunocompetent PDAC models Cancer research Medium 41066593
2026 FNDC4 regulates hepatic stellate cell (HSC) activation and fibrogenesis via the AMPK/YAP pathway: FNDC4 treatment attenuates TGF-β1-induced HSC collagen type I expression, apoptosis, and ROS production; increases MMP-1 and GATA4; inhibits TGF-β1-induced HSC migration by suppressing YAP expression and activation; AMPKα mediates FNDC4-induced elevation of mitochondrial DNA. Recombinant FNDC4 treatment of LX-2 HSCs, TGF-β1 stimulation model, collagen expression assay, ROS measurement, YAP western blot and activity assay, AMPKα mechanistic studies, migration assays Free radical biology & medicine Medium 41802610
2026 FNDC4 knockout in iPSC-derived forebrain neural organoids (via CRISPR/Cas9) causes a striking shift in the relative proportions of glutamatergic and GABAergic neurons and alters their electrical activity, indicating a role for FNDC4 in regulating cerebral cortical neurogenesis; FNDC4 alternative splicing results in loss of function; FNDC4 may mediate neural cell surface interactions. CRISPR/Cas9 KO, iPSC-derived neural organoids, single-nucleus RNA sequencing, electrophysiology, characterization of splice isoforms The Journal of clinical investigation Medium 41505223
2026 FNDC4 modulates colorectal cancer cell proliferation, migration, invasion, EMT, and M2 macrophage polarization via the Akt/STAT3 pathway; FNDC4 knockdown suppresses tumor growth and liver metastasis in vivo. FNDC4 knockdown in colorectal cancer cells, CCK8/clone formation/scratch/Transwell assays, flow cytometry for M2 markers, western blot for Akt/STAT3 pathway, xenograft tumor model Molecular and cellular endocrinology Low 41616831
2026 FNDC4 suppresses NF-κB pathway activation (phosphorylation-dependent) in LPS-stimulated macrophages, preserving their proliferation and migration and reducing apoptosis; exogenous FNDC4 alleviates sepsis-induced lung injury in vivo. Recombinant FNDC4 treatment of RAW264.7 macrophages, NF-κB phosphorylation western blot, proliferation/migration/apoptosis assays, septic rat model Molecular immunology Low 41819760
2025 Intrafollicular injection of recombinant FNDC4 into bovine first-wave growing follicles causes follicle regression in vivo; FNDC4 increases glucose uptake and GLUT1/GLUT3/GLUT4 mRNA in bovine granulosa cells in vitro; FNDC4 decreases lipid content in bovine theca cells in vitro without altering steroidogenesis. Ultrasound-guided intrafollicular injection in cattle, serum-free granulosa and theca cell culture, glucose uptake assay, RT-qPCR Animal reproduction science Low 41072083

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 139 12384288
2016 FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nature communications 89 27066907
2020 FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes. Metabolism: clinical and experimental 59 32407726
2021 Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. Nature communications 51 34016966
2018 FNDC4 Inhibits RANKL-Induced Osteoclast Formation by Suppressing NF-κB Activation and CXCL10 Expression. BioMed research international 17 29977911
2021 FNDC4 acts as an extracellular factor to promote the invasiveness of hepatocellular carcinoma partly via the PI3K/Akt signalling pathway. Cancer medicine 15 34418326
2024 FNDC4 reduces hepatocyte inflammatory cell death via AMPKα in metabolic dysfunction-associated steatotic liver disease. Clinical nutrition (Edinburgh, Scotland) 13 39173437
2024 FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice. Nature communications 13 39516487
2024 GRPR Drives Metastasis via CRABP2 and FNDC4 Pathways in Lung Adenocarcinoma. Cells 4 39768218
2023 FNDC4 reduces inflammation, proliferation, invasion and migration of rheumatoid synovial cells by inhibiting CCL2/ERK signaling. Tissue & cell 4 38181585
2026 FNDC4 regulates M2 polarization of tumor-associated macrophages to affect colorectal cancer metastasis. Molecular and cellular endocrinology 2 41616831
2025 FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function. JACC. Basic to translational science 2 40464727
2023 Overexpression of FNDC4 constrains ovarian cancer progression by promoting cell apoptosis and inhibiting cell growth. Journal of Cancer 2 38021165
2026 FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer. Cancer research 1 41066593
2026 FNDC4 modulates macrophage responses and suppresses NF-κB in sepsis-induced lung injury. Molecular immunology 1 41819760
2026 Alcohol use disorder-associated gene FNDC4 alters glutamatergic and GABAergic neurogenesis in neural organoids. The Journal of clinical investigation 0 41505223
2026 FNDC4 regulates TGF-β1-induced hepatic stellate cell activation and liver fibrosis via the AMPK/YAP pathway. Free radical biology & medicine 0 41802610
2026 FNDC4 and FNDC5 Attenuate SARS-CoV-2 S1-Induced Inflammatory Responses in Human Adipose Tissue. European journal of clinical investigation 0 42047312
2025 Alcohol Use Disorder Associated Gene FNDC4 Alters Glutamatergic and GABAergic Neurogenesis. bioRxiv : the preprint server for biology 0 40463052
2025 FNDC4 modulates in vitro bovine granulosa and theca cell metabolism and alters follicle development in vivo. Animal reproduction science 0 41072083
2024 The Role of FNDC4 in Inflammation and Metabolism for Various Diseases. Aging and disease 0 39325938

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