Affinage

FNDC4

Fibronectin type III domain-containing protein 4 · UniProt Q9H6D8

Length
234 aa
Mass
25.2 kDa
Annotated
2026-04-28
20 papers in source corpus 14 papers cited in narrative 14 extracted findings

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 and paracrine factor, dampening inflammation, modulating metabolism, and influencing cell fate decisions across multiple tissues. FNDC4 binds specifically to macrophages and monocytes to suppress NF-κB signaling and proinflammatory activity (PMID:27066907, PMID:41819760), signals through the adhesion GPCR GPR116 in white adipose tissue to promote insulin-mediated glucose uptake (PMID:34016966), and activates AMPKα-dependent pathways in hepatocytes and hepatic stellate cells to protect against inflammatory cell death, mitochondrial dysfunction, and fibrogenesis (PMID:39173437, PMID:41802610). In the heart, FNDC4 stabilizes HIF1α by preventing its proteasomal degradation and drives paracrine FGF1-mediated angiogenesis during ischemic injury, while AMPKα/PPARα signaling mediates its cardioprotective effects against age-related remodeling (PMID:39516487, PMID:40464727). FNDC4 also regulates cortical neurogenesis, as its knockout in human forebrain organoids shifts the balance of glutamatergic and GABAergic neurons (PMID:41505223).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Initial cloning established FNDC4 as a novel secreted protein with fibronectin type III domains, expressed in embryonic brain and adult heart, placing it as a candidate signaling factor with tissue-selective roles.

    Evidence Cloning and expression analysis of Frcp2 in mouse tissues

    PMID:12384288

    Open questions at the time
    • No functional data; purely descriptive expression and domain characterization
    • Receptor and downstream signaling unknown
  2. 2016 High

    The first functional characterization revealed that FNDC4 selectively binds macrophages/monocytes and acts as an anti-inflammatory factor — reducing phagocytosis, proinflammatory chemokine expression, and improving cell survival — establishing it as an immunomodulatory secreted protein.

    Evidence Binding assays across immune cell types, bone marrow-derived macrophage treatment, Fndc4 KO mice, recombinant protein rescue in mouse colitis model

    PMID:27066907

    Open questions at the time
    • Macrophage receptor for FNDC4 not identified
    • Intracellular signaling cascade mediating anti-inflammatory effects not defined
  3. 2018 Medium

    Extension of the anti-inflammatory mechanism to osteoclastogenesis showed FNDC4 suppresses NF-κB transcriptional activity and CXCL10 expression, identifying NF-κB as a key downstream target of FNDC4 action.

    Evidence NF-κB luciferase reporter, TRAP staining, bone resorption pit assay, CXCL10 rescue experiment in osteoclast precursors

    PMID:29977911

    Open questions at the time
    • Single lab; mechanism of NF-κB suppression (direct vs. indirect) not resolved
    • Receptor mediating effects on osteoclasts unknown
  4. 2020 Medium

    FNDC4 was shown to reduce lipid accumulation and promote browning gene expression in human visceral adipocytes, broadening its role to metabolic regulation and implicating GPR116 as a putative receptor in adipose tissue.

    Evidence FNDC4 knockdown and recombinant protein treatment in human visceral adipocytes, gene expression and mitochondrial DNA analysis

    PMID:32407726

    Open questions at the time
    • GPR116 dependency not directly tested with receptor knockout in this study
    • In vivo adipose browning phenotype not demonstrated
  5. 2021 High

    GPR116 was formally identified as the receptor for soluble FNDC4 in white adipose tissue through direct binding assays and GPR116 KO adipocytes, resolving the receptor question for metabolic signaling and demonstrating that FNDC4-GPR116 axis promotes insulin-mediated glucose uptake.

    Evidence Binding assays, GPR116 KO adipocytes, glucose uptake assays, prediabetic mouse model rescue with Fc-sFNDC4

    PMID:34016966

    Open questions at the time
    • Whether GPR116 mediates FNDC4 effects in macrophages or other tissues remains untested
    • Downstream G-protein or β-arrestin coupling not characterized
  6. 2024 High

    In the heart, FNDC4 was shown to stabilize HIF1α by blocking proteasomal degradation and to promote paracrine angiogenesis via FGF1 secretion from cardiomyocytes, establishing a cardioprotective mechanism during ischemia/reperfusion injury distinct from its metabolic and immune roles.

    Evidence Cardiac-specific FNDC4 overexpression and knockdown mice, proteasomal degradation assays, FGF1 secretion measurement, I/R injury model with recombinant FNDC4

    PMID:39516487

    Open questions at the time
    • Molecular mechanism by which FNDC4 inhibits HIF1α ubiquitination not elucidated
    • Whether GPR116 or another receptor mediates cardiac effects unknown
  7. 2024 Medium

    AMPKα was identified as a required mediator of FNDC4's cytoprotective effects in hepatocytes, where FNDC4 suppresses TNF-α-induced PANoptosis and NLRP3 inflammasome-driven pyroptosis while restoring mitochondrial function.

    Evidence FNDC4 knockdown and recombinant treatment in HepG2, AMPKα inhibition experiments, cell death and mitochondrial DNA assays

    PMID:39173437

    Open questions at the time
    • Direct AMPK activation mechanism (direct binding vs. upstream kinase) not defined
    • In vivo hepatoprotection not demonstrated in this study
  8. 2025 Medium

    The AMPKα/PPARα axis was shown to mediate FNDC4's cardioprotective effects against aging-related cardiac remodeling, linking the AMPK pathway identified in hepatocytes to cardiac function and establishing FNDC4 as a regulator of age-related mitochondrial and metabolic decline in the heart.

    Evidence Cardiac-specific overexpression and knockdown in aging mice, transcriptomics, untargeted metabolomics, AMPKα/PPARα pathway analysis

    PMID:40464727

    Open questions at the time
    • Whether FNDC4 activates AMPK through the same mechanism in heart and liver is unknown
    • Single lab
  9. 2026 Medium

    Multiple studies expanded FNDC4's mechanism: it suppresses hepatic stellate cell fibrogenesis via AMPKα/YAP, regulates cortical neurogenesis (glutamatergic/GABAergic neuron balance) in human forebrain organoids, stabilizes CCAR1/β-catenin signaling with unexpected nuclear localization in pancreatic cancer, and confirms NF-κB suppression as a conserved anti-inflammatory mechanism in sepsis-associated macrophage injury.

    Evidence CRISPR KO in iPSC-derived organoids with snRNA-seq (PMID:41505223); TGF-β1-stimulated LX-2 HSCs with YAP analysis (PMID:41802610); PDAC FNDC4 KD with CCAR1/β-catenin and macrophage polarization (PMID:41066593); LPS-stimulated macrophages and septic rat model (PMID:41819760)

    PMID:41066593 PMID:41505223 PMID:41802610 PMID:41819760

    Open questions at the time
    • Neural organoid findings lack identification of the receptor or direct molecular target mediating neurogenesis effects
    • Nuclear localization in PDAC is unexpected and requires independent confirmation
    • Whether FNDC4's anti-fibrotic YAP suppression occurs in vivo is untested
    • Unified signaling model across tissues remains absent

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: whether GPR116 is the universal receptor for FNDC4 across all responsive tissues (macrophages, heart, brain, liver); the structural basis for FNDC4-GPR116 interaction; the direct mechanism of AMPKα activation; and how FNDC4 achieves tissue-specific signaling outcomes despite using common downstream effectors such as NF-κB and AMPKα.
  • No structural model of FNDC4 or FNDC4-receptor complex
  • Receptor identity in macrophages, cardiomyocytes, and neurons not established
  • Direct versus indirect AMPKα activation mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 4 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2
Partners
AMPKACCAR1FGF1GPR116HIF1A

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 FNDC4 (Frcp2) was identified as a novel secreted protein containing fibronectin type III repeat domains, with expression primarily in the brain during embryonic development and in the heart in adult tissues. Cloning and expression analysis Gene Medium 12384288
2016 FNDC4 binds specifically to macrophages and monocytes (not other immune cell types), and treatment of bone marrow-derived macrophages reduces phagocytosis, increases cell survival, and reduces proinflammatory chemokine expression, resulting in dampened macrophage activity. Binding assays to immune cell types, in vitro BMDM treatment, recombinant protein administration in mouse colitis model, Fndc4 knockout mice Nature communications High 27066907
2021 The orphan adhesion GPCR GPR116 was identified as a direct receptor for soluble FNDC4 (sFNDC4) in white adipose tissue; sFNDC4 binds GPR116 with high affinity and promotes insulin signaling and insulin-mediated glucose uptake in white adipocytes in a GPR116-dependent manner. The liver primarily controls circulating sFNDC4 levels. Receptor identification via binding assays, GPR116 knockout adipocytes, glucose uptake assays, prediabetic mouse model rescue with FcsFNDC4 Nature communications High 34016966
2018 FNDC4 inhibits RANKL-induced osteoclastogenesis and mature osteoclast bone resorption in a dose-dependent manner by suppressing NF-κB transcriptional activity and downregulating CXCL10 expression; supplementation of CXCL10 partially rescues FNDC4-mediated inhibition. TRAP staining, bone resorption pit assay, NF-κB luciferase reporter assay, western blotting, CXCL10 rescue experiment BioMed research international Medium 29977911
2020 FNDC4 reduces intracytosolic lipid accumulation and stimulates brown-like gene expression (UCP-1, PRDM16, TMEM26, CD137) in human visceral adipocytes; FNDC4 knockdown increases lipogenesis and reduces brown/beige markers and mitochondrial biogenesis factors. GPR116 was identified as a putative receptor in visceral adipose tissue. FNDC4 knockdown in human adipocytes, recombinant FNDC4 treatment, gene expression analysis, mitochondrial DNA quantification Metabolism: clinical and experimental Medium 32407726
2021 FNDC4, acting as an extracellular factor, promotes Akt phosphorylation via the PI3K/Akt signaling pathway to enhance migration and invasion of hepatocellular carcinoma cells. Recombinant extracellular domain treatment, western blotting for Akt phosphorylation, migration/invasion assays Cancer medicine Low 34418326
2024 FNDC4 regulates proteasomal degradation of HIF1α in cardiomyocytes; cardiac-specific FNDC4 overexpression stabilizes HIF1α to promote cardiomyocyte survival and angiogenesis during ischemia/reperfusion injury. FNDC4 does not directly stimulate endothelial angiogenesis but increases FGF1 secretion from cardiomyocytes in a paracrine manner. Cardiac-specific FNDC4 overexpression and knockdown mouse models, proteasomal degradation assays, FGF1 secretion measurement, I/R injury model with recombinant FNDC4 administration Nature communications High 39516487
2024 FNDC4 reduces TNF-α-induced PANoptosis (pyroptosis, apoptosis, necroptosis) and NLRP3 inflammasome-induced pyroptosis in hepatocytes; AMPKα is required for FNDC4-mediated inhibition of cell death and improvement of mitochondrial DNA content. FNDC4 also improves mitochondrial dysfunction by enhancing OXPHOS complex subunit expression. FNDC4 knockdown and recombinant FNDC4 treatment in HepG2 cells, AMPKα inhibition experiments, cell death assays (apoptosis, pyroptosis, necroptosis), mitochondrial DNA quantification, western blotting Clinical nutrition (Edinburgh, Scotland) Medium 39173437
2023 FNDC4 overexpression in rheumatoid arthritis fibroblast-like synoviocytes inhibits their proliferation, invasion, migration, and inflammatory cytokine release by suppressing the CCL2/ERK signaling pathway. FNDC4 overexpression plasmid, wound healing and transwell assays, ERK pathway activator rescue (tBHQ), CCL2 overexpression rescue, western blotting Tissue & cell Medium 38181585
2025 FNDC4 activates AMPKα/PPARα signaling in aging cardiomyocytes to restore mitochondrial function and reduce lipotoxicity; cardiac-specific FNDC4 overexpression alleviates while knockdown worsens aging-related cardiac remodeling and dysfunction. Cardiac-specific overexpression and knockdown in aging mice, transcriptome analysis, untargeted metabolomics, western blotting for AMPKα/PPARα pathway JACC. Basic to translational science Medium 40464727
2026 FNDC4 enhances CCAR1 protein stability to sustain CCAR1/β-catenin signaling in pancreatic cancer cells, promoting invasion and colony formation; FNDC4 also drives macrophage polarization toward M2 phenotype and promotes immune evasion. FNDC4 unexpectedly localizes to the nucleus in PDAC cells. CCL5 is identified as a critical downstream effector mediating immune effects, and BHLHE40 directly activates FNDC4 transcription upstream. FNDC4 knockdown in PDAC models, CCAR1/β-catenin western blotting, macrophage polarization assays, T-cell infiltration analysis, transcriptomic analysis, immunofluorescence for nuclear localization, ChIP or transcription factor binding for BHLHE40 Cancer research Medium 41066593
2026 FNDC4 inhibits TGF-β1-driven hepatic stellate cell (HSC) activation and fibrogenesis via AMPKα/YAP pathway: FNDC4 suppresses YAP expression and activation (a downstream AMPK target) to inhibit HSC migration, reduces collagen type I, and increases MMP-1 and GATA4. AMPKα mediates FNDC4-induced mitochondrial DNA elevation in HSCs. FNDC4 treatment of human LX-2 HSCs, TGF-β1 stimulation model, AMPKα pathway analysis, YAP expression/activation western blotting, migration assays, MMP-1/GATA4 measurements Free radical biology & medicine Medium 41802610
2026 FNDC4 knockout in human iPSC-derived forebrain neural organoids causes a striking shift in the balance of glutamatergic vs. GABAergic neurons and alters electrical activity, indicating a role for FNDC4 in regulating cortical neurogenesis, potentially through mediating neural cell surface interactions. CRISPR/Cas9 KO of FNDC4 in human iPSC-derived forebrain organoids, single-nucleus RNA sequencing, electrophysiology The Journal of clinical investigation Medium 41505223
2026 FNDC4 suppresses NF-κB pathway phosphorylation-dependent activation in LPS-stimulated macrophages, preserving macrophage proliferation and migration while reducing apoptosis, and alleviates sepsis-induced lung injury in vivo. LPS-stimulated RAW264.7 macrophage treatment with recombinant FNDC4, NF-κB phosphorylation western blotting, septic rat model, cell proliferation/migration/apoptosis assays Molecular immunology Medium 41819760

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 138 12384288
2016 FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nature communications 86 27066907
2020 FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes. Metabolism: clinical and experimental 56 32407726
2021 Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue. Nature communications 48 34016966
2018 FNDC4 Inhibits RANKL-Induced Osteoclast Formation by Suppressing NF-κB Activation and CXCL10 Expression. BioMed research international 16 29977911
2021 FNDC4 acts as an extracellular factor to promote the invasiveness of hepatocellular carcinoma partly via the PI3K/Akt signalling pathway. Cancer medicine 14 34418326
2024 FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice. Nature communications 13 39516487
2024 FNDC4 reduces hepatocyte inflammatory cell death via AMPKα in metabolic dysfunction-associated steatotic liver disease. Clinical nutrition (Edinburgh, Scotland) 11 39173437
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 3 38181585
2023 Overexpression of FNDC4 constrains ovarian cancer progression by promoting cell apoptosis and inhibiting cell growth. Journal of Cancer 2 38021165
2025 FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function. JACC. Basic to translational science 1 40464727
2026 FNDC4 Drives Metastasis and Immune Evasion in Pancreatic Cancer. Cancer research 0 41066593
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 M2 polarization of tumor-associated macrophages to affect colorectal cancer metastasis. Molecular and cellular endocrinology 0 41616831
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 modulates macrophage responses and suppresses NF-κB in sepsis-induced lung injury. Molecular immunology 0 41819760
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