{"gene":"CERS3","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2006,"finding":"CERS3 (LASS3) encodes a (dihydro)ceramide synthase with relatively broad substrate specificity, preferring middle- to long-chain fatty acyl-CoAs (C16–C26 range). Overexpression in vivo increased several ceramide species, confirmed by in vitro ceramide synthase assay.","method":"In vivo [3H]dihydrosphingosine labeling, electrospray-ionization MS, in vitro (dihydro)ceramide synthase assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay plus in vivo labeling, foundational characterization paper","pmids":["16753040"],"is_preprint":false},{"year":2008,"finding":"CERS3 mRNA expression is restricted to germ cells in the testis and is upregulated >700-fold during postnatal testicular maturation; CERS3 drives synthesis of very long-chain polyunsaturated fatty acid (VLC-PUFA, C26–C32) sphingolipids required for male meiosis and spermatogenesis.","method":"Quantitative RT-PCR, lipidomic analysis of male sterile mutants with spermatogenic arrest at defined stages, correlation with sphingolipid profiles","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple mutant models with defined stage-specific arrest correlated with CERS3 expression and lipid profiles, replicated across models","pmids":["18308723"],"is_preprint":false},{"year":2008,"finding":"CerS3/LASS3 mRNA is the most predominantly expressed ceramide synthase in keratinocytes, its expression increases upon differentiation, and all CerS members including CerS3 can produce 2-hydroxy-ceramide with chain-length specificity matching their respective non-hydroxy ceramide products.","method":"Quantitative RT-PCR, overexpression in HEK 293T cells, in vitro CerS assay with 2-hydroxy-fatty acyl-CoA substrates","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic assay combined with cell expression studies and KD confirmation","pmids":["18541923"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in CERS3 cause autosomal recessive congenital ichthyosis by abolishing ceramide synthase activity toward C26-CoA, resulting in specific loss of very long chain ceramides (C26–C34) in terminally differentiating keratinocytes and disruption of epidermal barrier function.","method":"Autozygosity mapping, exome sequencing, in vitro N-acylation assay with C26-CoA in patient keratinocytes and recombinant mutant proteins, lipidomic profiling of patient keratinocytes, reconstructed patient skin analysis","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic assay with patient and recombinant mutant proteins, multiple orthogonal methods, independently replicated","pmids":["23549421"],"is_preprint":false},{"year":2013,"finding":"CERS3 mutations (homozygous deletion and splice site mutation) cause ARCI by disrupting sphingolipid metabolism with reduced levels of epidermis-specific very long-chain ceramides, interfering with epidermal differentiation and lipid homeostasis.","method":"Genome-wide SNP-genotyping, exome sequencing, sphingolipid profiling in patient skin and in vitro differentiated keratinocytes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — independent cohort replicating the enzymatic and lipid phenotype of CERS3 loss-of-function","pmids":["23754960"],"is_preprint":false},{"year":2013,"finding":"CERS3 and ELOVL4 are coordinately upregulated during keratinocyte differentiation via PPARβ/δ; CERS3 knockdown reduces elongase activity toward ultra-long-chain acyl-CoAs, indicating CERS3 positively regulates ULCFA synthesis.","method":"In vivo and in vitro mRNA expression analysis, siRNA knockdown of CERS3, elongase activity assay","journal":"PLoS one","confidence":"High","confidence_rationale":"Tier 1–2 — KD with enzymatic readout plus transcriptional regulation analysis","pmids":["23826266"],"is_preprint":false},{"year":2013,"finding":"ELOVL1 is required for producing C26+ fatty acids used by CerS2 and CerS3 in the epidermis; layer-specific expression of CerS2 and CerS3 regulates acyl-CoA chain-length inputs for ceramide production, establishing ELOVL1 as upstream of CerS3 in the epidermal ceramide biosynthetic pathway.","method":"Elovl1 knockout mouse generation, lipidomic analysis of epidermis, immunohistochemistry for CerS2 and CerS3 expression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in KO mouse with lipidomic confirmation of pathway position","pmids":["23689133"],"is_preprint":false},{"year":2015,"finding":"CerS3 localizes to pachytene spermatocytes until completion of meiosis and to elongating spermatids; loss of CerS3 in mice causes spermatogenic arrest with enhanced apoptosis during meiosis and formation of multinuclear giant cells, linked to loss of sphingolipids with ultra-long polyunsaturated anchors required for intercellular bridge stability.","method":"High-resolution mass spectrometric imaging (in situ), CerS3-KO mice, glucosylceramide synthase-KO mice, immunolocalization of CerS3","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 — in situ MS imaging, KO mouse with defined cellular phenotype, multiple genetic models","pmids":["26045466"],"is_preprint":false},{"year":2016,"finding":"CERS3 enzyme activity is regulated by phosphorylation at its cytoplasmic C-terminal region; dephosphorylation (via CK2 inhibitor CX-4945) modestly reduces CERS3 catalytic activity, with most phosphorylated residues conforming to a CK2 consensus motif.","method":"Phosphorylation analysis, CK2 inhibitor treatment (CX-4945), in vitro ceramide synthase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity assay combined with pharmacological inhibition of the kinase writer","pmids":["26887952"],"is_preprint":false},{"year":2017,"finding":"Acyl-CoA-binding protein (ACBP) binds very-long-chain acyl-CoA esters and stimulates CerS3 activity by ~7-fold; ACBP physically interacts with CerS3, and CerS3 activity is significantly reduced in testes of ACBP-knockout mice along with reduced long- and very-long-chain ceramide levels.","method":"In vitro ceramide synthase assay with liver cytosol from WT and ACBP-KO mice, Co-immunoprecipitation (ACBP with CerS3), lipid mass spectrometry in ACBP-KO testes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic assay, reciprocal Co-IP, and genetic KO model with lipidomic confirmation","pmids":["28320857"],"is_preprint":false},{"year":2017,"finding":"The complete biosynthetic pathway for acylceramide in epidermis was established: ELOVL1 and ELOVL4 synthesize ultra-long-chain fatty acids (ULCFA), CYP4F22 ω-hydroxylates ULCFA, CERS3 forms the amide bond with a long-chain base, and PNPLA1 transacylates linoleic acid to produce acylceramide.","method":"Genetic pathway analysis, in vitro reconstitution of enzymatic steps, mutant protein analysis","journal":"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan","confidence":"High","confidence_rationale":"Tier 1 — biochemical pathway reconstitution with genetic validation placing CERS3 in a defined biosynthetic sequence","pmids":["28966260"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous CERS3 mutations (nonsense p.Arg75* and missense p.Arg229His) reduce ceramide synthase activity to 4% and 56% of wild-type, respectively; patient stratum corneum shows greatly reduced acylceramide levels while protein-bound ceramide levels remain nearly unchanged, demonstrating that acylceramide reduction alone is sufficient to cause ichthyosis.","method":"In vitro ceramide synthase activity assay of recombinant mutant CERS3 proteins, comprehensive stratum corneum ceramide profiling by mass spectrometry","journal":"The Journal of dermatology","confidence":"High","confidence_rationale":"Tier 1 — direct enzymatic assay of recombinant mutant proteins with quantitative lipidomic phenotyping","pmids":["33492757"],"is_preprint":false},{"year":2022,"finding":"S1PR1 promotes angiogenesis by decreasing ceramide levels via CerS3 downregulation; mechanistically, S1PR1 induces CerS6 nuclear translocation which transcriptionally inhibits CerS3 in endothelial cells.","method":"siRNA knockdown, overexpression experiments, nuclear fractionation, in vitro and in vivo angiogenesis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic pathway placement with nuclear translocation and transcriptional regulation demonstrated, single lab","pmids":["36068200"],"is_preprint":false},{"year":2022,"finding":"In diabetic kidney disease, CFB deficiency reduces NF-κB p65 activation, which normally drives transcription of CERS3; inhibiting this pathway reduces ceramide biosynthesis and attenuates tubulointerstitial injury.","method":"siRNA knockdown of CFB in HK-2 cells, Cfb-knockout diabetic mice, ceramide synthase inhibitor (fumonisin B1), NF-κB signaling analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological approaches in vitro and in vivo, but NF-κB→CERS3 transcriptional link is based on expression analysis without direct promoter studies","pmids":["36546481"],"is_preprint":false},{"year":2025,"finding":"CERS3 produces C26 ceramide (d18:1/26:0) which activates epidermal growth factor receptor (EGFR) by binding its extracellular region to promote cancer cell proliferation; bacterial riboflavin from Bacteroides cellulosilyticus inhibits CERS3 activity, reducing C26 ceramide and delaying colorectal cancer progression; aclidinium bromide also inhibits CERS3 activity.","method":"CERS3 overexpression/knockdown in CRC cells, EGFR binding assay, ceramide mass spectrometry, riboflavin-CERS3 activity inhibition assay, aclidinium bromide CERS3 activity assay, mouse CRC models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzymatic inhibition assay, direct EGFR binding by ceramide product, multiple genetic and pharmacological approaches with in vivo validation","pmids":["40609532"],"is_preprint":false},{"year":2025,"finding":"CerS3 (mammalian) expressed in yeast supports near-normal nutrient-dependent cell size modulation through production of C24–C26 ceramides, demonstrating that CERS3 substrate specificity for very-long-chain ceramides determines downstream TORC2 signaling and cell size control.","method":"Expression of mammalian CerS3 in yeast elongation mutants (elo3Δ), TORC2 signaling readout (Ypk1/2 pT662), cell size measurement under nutrient deprivation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution in yeast with functional readout, but preprint and uses heterologous system","pmids":["bio_10.1101_2025.11.28.691118"],"is_preprint":true},{"year":2025,"finding":"Inducible knockdown of CerS3 in 3D human skin equivalents reduces polar lipid staining and causes a specific reduction in ultra-long-chain ceramide classes and chain lengths without disrupting stratification or terminal differentiation, confirming CerS3's specific role in ultra-long-chain ceramide synthesis for epidermal barrier lipid composition.","method":"Doxycycline-inducible shRNA knockdown of CerS3 in N/TERT keratinocytes in 3D HSEs, mass spectrometry lipidomics, Nile Red staining","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean inducible KD with lipidomic readout in 3D skin model, but preprint","pmids":["bio_10.1101_2025.01.20.633956"],"is_preprint":true},{"year":2022,"finding":"CerS3 overexpression promotes HCC cell proliferation, migration, and invasion via activation of the SMAD6 gene, as determined by RNA sequencing of downstream targets.","method":"Retroviral overexpression and lentiviral shRNA knockdown of CerS3 in HCC cell lines (Hep3B, HCCLM3), MTT/EdU proliferation assays, Transwell invasion assay, RNA sequencing","journal":"Zhong nan da xue xue bao. Yi xue ban","confidence":"Low","confidence_rationale":"Tier 3 — single lab, overexpression/KD with downstream transcriptomic analysis but no direct biochemical link established","pmids":["35753729"],"is_preprint":false}],"current_model":"CERS3 is a ceramide synthase that catalyzes the amide-bond formation between a long-chain sphingoid base and ultra-long-chain fatty acyl-CoAs (C26–C36, produced upstream by ELOVL1/ELOVL4), generating very-long-chain and acylceramides essential for epidermal permeability barrier formation and male germ cell meiosis; its activity is stimulated by ACBP (which delivers very-long-chain acyl-CoA substrates) and is regulated by CK2-mediated phosphorylation of its C-terminal region, while its transcription is controlled by PPARβ/δ during keratinocyte differentiation and repressed by nuclear CerS6 in endothelial cells downstream of S1PR1 signaling."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing CERS3 as a bona fide ceramide synthase with relatively broad acyl-CoA specificity (C16–C26) resolved the question of whether this uncharacterized LASS family member possessed intrinsic (dihydro)ceramide synthase activity.","evidence":"In vivo [³H]dihydrosphingosine labeling and in vitro ceramide synthase assay upon overexpression","pmids":["16753040"],"confidence":"High","gaps":["Preferred substrates in native tissues not yet defined","No structural basis for substrate recognition"]},{"year":2008,"claim":"Identification of CERS3 as the dominant ceramide synthase in both testicular germ cells and differentiating keratinocytes established its tissue-specific roles in generating VLC-PUFA sphingolipids for spermatogenesis and 2-hydroxy-ceramides for epidermis.","evidence":"qRT-PCR expression profiling in testis and keratinocytes; lipidomic analysis of spermatogenic mutants; in vitro assays with 2-hydroxy-fatty acyl-CoA substrates","pmids":["18308723","18541923"],"confidence":"High","gaps":["Direct genetic proof of CERS3 requirement in each tissue not yet available","Mechanism by which CERS3 accommodates 2-hydroxy substrates unknown"]},{"year":2013,"claim":"Discovery that homozygous loss-of-function CERS3 mutations cause autosomal recessive congenital ichthyosis (ARCI) through depletion of C26–C34 ceramides proved CERS3 is essential for epidermal barrier function and positioned it in a defined biosynthetic pathway with ELOVL1 and PPARβ/δ.","evidence":"Exome sequencing of ARCI families, in vitro enzymatic assays of patient and recombinant mutant proteins, lipidomic profiling of patient keratinocytes, ELOVL1-KO mouse epistasis, PPARβ/δ regulation by siRNA and expression analysis","pmids":["23549421","23754960","23826266","23689133"],"confidence":"High","gaps":["Direct promoter binding by PPARβ/δ not demonstrated","Contribution of individual ultra-long-chain species to barrier function not resolved"]},{"year":2015,"claim":"CerS3-knockout mice revealed that CerS3 is required for meiotic progression and intercellular bridge stability in spermatocytes, confirming a cell-autonomous role in male fertility through production of sphingolipids with ultra-long polyunsaturated anchors.","evidence":"CerS3-KO mice with in situ mass spectrometric imaging and immunolocalization in pachytene spermatocytes and elongating spermatids","pmids":["26045466"],"confidence":"High","gaps":["Specific sphingolipid species mediating intercellular bridge stability not identified","Whether human male infertility results from CERS3 mutations is untested"]},{"year":2016,"claim":"Demonstration that CK2-mediated phosphorylation of the CERS3 C-terminal region modulates catalytic activity established a post-translational regulatory mechanism for this enzyme.","evidence":"CK2 inhibitor (CX-4945) treatment followed by in vitro ceramide synthase activity assay and phospho-mapping","pmids":["26887952"],"confidence":"High","gaps":["Magnitude of regulation is modest; physiological contexts where this matters are unclear","Individual phospho-site contributions not dissected by mutagenesis"]},{"year":2017,"claim":"Identification of ACBP as a physical interactor that delivers very-long-chain acyl-CoA to CerS3 and stimulates its activity ~7-fold resolved how substrate supply is coupled to ceramide synthesis, and placement of CERS3 within the complete acylceramide biosynthetic pathway (ELOVL1/4→CYP4F22→CERS3→PNPLA1) defined its precise enzymatic step.","evidence":"Co-immunoprecipitation of ACBP with CerS3, in vitro assays in ACBP-KO liver cytosol and testes lipidomics; biochemical pathway reconstitution","pmids":["28320857","28966260"],"confidence":"High","gaps":["Structural basis of ACBP–CerS3 interaction unknown","Whether ACBP regulation is tissue-specific (skin vs. testis) not compared"]},{"year":2021,"claim":"Quantitative enzymatic analysis of compound heterozygous CERS3 mutations demonstrated that reduction in acylceramide—not protein-bound ceramide—is sufficient to cause ichthyosis, refining the genotype-phenotype relationship.","evidence":"In vitro ceramide synthase assay of recombinant R75* and R229H mutant proteins with stratum corneum ceramide profiling by mass spectrometry","pmids":["33492757"],"confidence":"High","gaps":["Threshold of residual activity needed to prevent disease not defined","Whether modifier genes modulate phenotypic severity is unknown"]},{"year":2022,"claim":"Transcriptional repression of CERS3 by nuclear CerS6 downstream of S1PR1 signaling in endothelial cells revealed an inter-CerS regulatory circuit linking sphingolipid metabolism to angiogenesis.","evidence":"siRNA knockdown and overexpression with nuclear fractionation in endothelial cells; in vitro and in vivo angiogenesis assays","pmids":["36068200"],"confidence":"Medium","gaps":["Direct CerS6 binding to CERS3 promoter not shown","Not independently replicated","Relevance to in vivo vascular biology beyond tumor angiogenesis untested"]},{"year":2025,"claim":"Discovery that CERS3-produced C26 ceramide directly binds and activates EGFR to promote colorectal cancer cell proliferation, inhibitable by bacterial riboflavin or aclidinium bromide, extended CERS3 function to oncogenic signaling and identified the first pharmacological inhibitors of this enzyme.","evidence":"CERS3 overexpression/knockdown in CRC cells, EGFR extracellular domain binding assay, ceramide MS, riboflavin and aclidinium bromide inhibition assays, mouse CRC models","pmids":["40609532"],"confidence":"High","gaps":["Selectivity of CERS3 inhibitors over other CerS family members not characterized","Whether C26 ceramide–EGFR binding occurs under physiological lipid concentrations is uncertain","Structural mechanism of EGFR activation by C26 ceramide unknown"]},{"year":null,"claim":"Key unresolved questions include the three-dimensional structure of CERS3, the molecular basis of its ultra-long-chain acyl-CoA selectivity, the full scope of post-translational regulatory mechanisms, and whether CERS3 inhibition is therapeutically viable in cancer without compromising skin or testicular barrier function.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure available","Mechanism of acyl-chain length selectivity unresolved","Therapeutic window for CERS3 inhibition not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,8,9,11,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,6,9,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,14]}],"complexes":[],"partners":["ACBP","ELOVL1","ELOVL4","CYP4F22","PNPLA1","CERS6"],"other_free_text":[]},"mechanistic_narrative":"CERS3 is a ceramide synthase that catalyzes amide-bond formation between long-chain sphingoid bases and very-long-chain to ultra-long-chain fatty acyl-CoAs (C24–C36), generating the very-long-chain ceramides and acylceramide precursors essential for epidermal permeability barrier formation and male germ cell meiosis [PMID:16753040, PMID:23549421, PMID:26045466, PMID:28966260]. In the epidermis, CERS3 operates downstream of ELOVL1/ELOVL4-mediated fatty acid elongation and upstream of PNPLA1-catalyzed acylceramide completion; its transcription is induced by PPARβ/δ during keratinocyte differentiation, and its enzymatic activity is stimulated ~7-fold by acyl-CoA-binding protein (ACBP) and modestly regulated by CK2-mediated C-terminal phosphorylation [PMID:23826266, PMID:23689133, PMID:28320857, PMID:26887952]. Loss-of-function mutations in CERS3 cause autosomal recessive congenital ichthyosis (ARCI) through specific depletion of ultra-long-chain and acylceramides in the stratum corneum [PMID:23549421, PMID:23754960, PMID:33492757]. CERS3-produced C26 ceramide can also activate EGFR signaling to promote colorectal cancer cell proliferation, a pathway inhibitable by bacterial riboflavin or aclidinium bromide [PMID:40609532]."},"prefetch_data":{"uniprot":{"accession":"Q8IU89","full_name":"Ceramide synthase 3","aliases":["Dihydroceramide synthase 3","LAG1 longevity assurance homolog 3","Sphingosine N-acyltransferase CERS3","Ultra-long-chain ceramide synthase CERS3","Very-long-chain ceramide synthase CERS3"],"length_aa":383,"mass_kda":46.3,"function":"Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22) (PubMed:17977534, PubMed:22038835, PubMed:26887952). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:22038835, PubMed:26887952). It is crucial for the synthesis of ultra-long-chain ceramides in the epidermis, to maintain epidermal lipid homeostasis and terminal differentiation (PubMed:23754960)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8IU89/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CERS3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CERS3","total_profiled":1310},"omim":[{"mim_id":"615276","title":"CERAMIDE SYNTHASE 3; CERS3","url":"https://www.omim.org/entry/615276"},{"mim_id":"615023","title":"ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 9; ARCI9","url":"https://www.omim.org/entry/615023"},{"mim_id":"613195","title":"WEILL-MARCHESANI SYNDROME 4; WMS4","url":"https://www.omim.org/entry/613195"},{"mim_id":"611813","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 1; ELOVL1","url":"https://www.omim.org/entry/611813"},{"mim_id":"242300","title":"ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1; ARCI1","url":"https://www.omim.org/entry/242300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":53.1},{"tissue":"skin 1","ntpm":61.6},{"tissue":"vagina","ntpm":29.4}],"url":"https://www.proteinatlas.org/search/CERS3"},"hgnc":{"alias_symbol":["MGC27091"],"prev_symbol":["LASS3"]},"alphafold":{"accession":"Q8IU89","domains":[{"cath_id":"-","chopping":"24-67_127-333","consensus_level":"high","plddt":93.498,"start":24,"end":333},{"cath_id":"1.10.10.60","chopping":"82-125","consensus_level":"high","plddt":89.9711,"start":82,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU89","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU89-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU89-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CERS3","jax_strain_url":"https://www.jax.org/strain/search?query=CERS3"},"sequence":{"accession":"Q8IU89","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IU89.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IU89/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU89"}},"corpus_meta":[{"pmid":"16753040","id":"PMC_16753040","title":"LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16753040","citation_count":157,"is_preprint":false},{"pmid":"23689133","id":"PMC_23689133","title":"Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23689133","citation_count":144,"is_preprint":false},{"pmid":"23549421","id":"PMC_23549421","title":"Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23549421","citation_count":133,"is_preprint":false},{"pmid":"23754960","id":"PMC_23754960","title":"Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23754960","citation_count":131,"is_preprint":false},{"pmid":"28571749","id":"PMC_28571749","title":"Altered expression of epidermal lipid bio-synthesis enzymes in atopic dermatitis skin is accompanied by changes in stratum corneum lipid composition.","date":"2017","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/28571749","citation_count":107,"is_preprint":false},{"pmid":"20304771","id":"PMC_20304771","title":"A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.","date":"2010","source":"The journals of gerontology. 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Overexpression in vivo increased several ceramide species, confirmed by in vitro ceramide synthase assay.\",\n      \"method\": \"In vivo [3H]dihydrosphingosine labeling, electrospray-ionization MS, in vitro (dihydro)ceramide synthase assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay plus in vivo labeling, foundational characterization paper\",\n      \"pmids\": [\"16753040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CERS3 mRNA expression is restricted to germ cells in the testis and is upregulated >700-fold during postnatal testicular maturation; CERS3 drives synthesis of very long-chain polyunsaturated fatty acid (VLC-PUFA, C26–C32) sphingolipids required for male meiosis and spermatogenesis.\",\n      \"method\": \"Quantitative RT-PCR, lipidomic analysis of male sterile mutants with spermatogenic arrest at defined stages, correlation with sphingolipid profiles\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mutant models with defined stage-specific arrest correlated with CERS3 expression and lipid profiles, replicated across models\",\n      \"pmids\": [\"18308723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CerS3/LASS3 mRNA is the most predominantly expressed ceramide synthase in keratinocytes, its expression increases upon differentiation, and all CerS members including CerS3 can produce 2-hydroxy-ceramide with chain-length specificity matching their respective non-hydroxy ceramide products.\",\n      \"method\": \"Quantitative RT-PCR, overexpression in HEK 293T cells, in vitro CerS assay with 2-hydroxy-fatty acyl-CoA substrates\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic assay combined with cell expression studies and KD confirmation\",\n      \"pmids\": [\"18541923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in CERS3 cause autosomal recessive congenital ichthyosis by abolishing ceramide synthase activity toward C26-CoA, resulting in specific loss of very long chain ceramides (C26–C34) in terminally differentiating keratinocytes and disruption of epidermal barrier function.\",\n      \"method\": \"Autozygosity mapping, exome sequencing, in vitro N-acylation assay with C26-CoA in patient keratinocytes and recombinant mutant proteins, lipidomic profiling of patient keratinocytes, reconstructed patient skin analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic assay with patient and recombinant mutant proteins, multiple orthogonal methods, independently replicated\",\n      \"pmids\": [\"23549421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CERS3 mutations (homozygous deletion and splice site mutation) cause ARCI by disrupting sphingolipid metabolism with reduced levels of epidermis-specific very long-chain ceramides, interfering with epidermal differentiation and lipid homeostasis.\",\n      \"method\": \"Genome-wide SNP-genotyping, exome sequencing, sphingolipid profiling in patient skin and in vitro differentiated keratinocytes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent cohort replicating the enzymatic and lipid phenotype of CERS3 loss-of-function\",\n      \"pmids\": [\"23754960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CERS3 and ELOVL4 are coordinately upregulated during keratinocyte differentiation via PPARβ/δ; CERS3 knockdown reduces elongase activity toward ultra-long-chain acyl-CoAs, indicating CERS3 positively regulates ULCFA synthesis.\",\n      \"method\": \"In vivo and in vitro mRNA expression analysis, siRNA knockdown of CERS3, elongase activity assay\",\n      \"journal\": \"PLoS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KD with enzymatic readout plus transcriptional regulation analysis\",\n      \"pmids\": [\"23826266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELOVL1 is required for producing C26+ fatty acids used by CerS2 and CerS3 in the epidermis; layer-specific expression of CerS2 and CerS3 regulates acyl-CoA chain-length inputs for ceramide production, establishing ELOVL1 as upstream of CerS3 in the epidermal ceramide biosynthetic pathway.\",\n      \"method\": \"Elovl1 knockout mouse generation, lipidomic analysis of epidermis, immunohistochemistry for CerS2 and CerS3 expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in KO mouse with lipidomic confirmation of pathway position\",\n      \"pmids\": [\"23689133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CerS3 localizes to pachytene spermatocytes until completion of meiosis and to elongating spermatids; loss of CerS3 in mice causes spermatogenic arrest with enhanced apoptosis during meiosis and formation of multinuclear giant cells, linked to loss of sphingolipids with ultra-long polyunsaturated anchors required for intercellular bridge stability.\",\n      \"method\": \"High-resolution mass spectrometric imaging (in situ), CerS3-KO mice, glucosylceramide synthase-KO mice, immunolocalization of CerS3\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in situ MS imaging, KO mouse with defined cellular phenotype, multiple genetic models\",\n      \"pmids\": [\"26045466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CERS3 enzyme activity is regulated by phosphorylation at its cytoplasmic C-terminal region; dephosphorylation (via CK2 inhibitor CX-4945) modestly reduces CERS3 catalytic activity, with most phosphorylated residues conforming to a CK2 consensus motif.\",\n      \"method\": \"Phosphorylation analysis, CK2 inhibitor treatment (CX-4945), in vitro ceramide synthase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity assay combined with pharmacological inhibition of the kinase writer\",\n      \"pmids\": [\"26887952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Acyl-CoA-binding protein (ACBP) binds very-long-chain acyl-CoA esters and stimulates CerS3 activity by ~7-fold; ACBP physically interacts with CerS3, and CerS3 activity is significantly reduced in testes of ACBP-knockout mice along with reduced long- and very-long-chain ceramide levels.\",\n      \"method\": \"In vitro ceramide synthase assay with liver cytosol from WT and ACBP-KO mice, Co-immunoprecipitation (ACBP with CerS3), lipid mass spectrometry in ACBP-KO testes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic assay, reciprocal Co-IP, and genetic KO model with lipidomic confirmation\",\n      \"pmids\": [\"28320857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The complete biosynthetic pathway for acylceramide in epidermis was established: ELOVL1 and ELOVL4 synthesize ultra-long-chain fatty acids (ULCFA), CYP4F22 ω-hydroxylates ULCFA, CERS3 forms the amide bond with a long-chain base, and PNPLA1 transacylates linoleic acid to produce acylceramide.\",\n      \"method\": \"Genetic pathway analysis, in vitro reconstitution of enzymatic steps, mutant protein analysis\",\n      \"journal\": \"Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical pathway reconstitution with genetic validation placing CERS3 in a defined biosynthetic sequence\",\n      \"pmids\": [\"28966260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous CERS3 mutations (nonsense p.Arg75* and missense p.Arg229His) reduce ceramide synthase activity to 4% and 56% of wild-type, respectively; patient stratum corneum shows greatly reduced acylceramide levels while protein-bound ceramide levels remain nearly unchanged, demonstrating that acylceramide reduction alone is sufficient to cause ichthyosis.\",\n      \"method\": \"In vitro ceramide synthase activity assay of recombinant mutant CERS3 proteins, comprehensive stratum corneum ceramide profiling by mass spectrometry\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct enzymatic assay of recombinant mutant proteins with quantitative lipidomic phenotyping\",\n      \"pmids\": [\"33492757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S1PR1 promotes angiogenesis by decreasing ceramide levels via CerS3 downregulation; mechanistically, S1PR1 induces CerS6 nuclear translocation which transcriptionally inhibits CerS3 in endothelial cells.\",\n      \"method\": \"siRNA knockdown, overexpression experiments, nuclear fractionation, in vitro and in vivo angiogenesis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic pathway placement with nuclear translocation and transcriptional regulation demonstrated, single lab\",\n      \"pmids\": [\"36068200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In diabetic kidney disease, CFB deficiency reduces NF-κB p65 activation, which normally drives transcription of CERS3; inhibiting this pathway reduces ceramide biosynthesis and attenuates tubulointerstitial injury.\",\n      \"method\": \"siRNA knockdown of CFB in HK-2 cells, Cfb-knockout diabetic mice, ceramide synthase inhibitor (fumonisin B1), NF-κB signaling analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches in vitro and in vivo, but NF-κB→CERS3 transcriptional link is based on expression analysis without direct promoter studies\",\n      \"pmids\": [\"36546481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CERS3 produces C26 ceramide (d18:1/26:0) which activates epidermal growth factor receptor (EGFR) by binding its extracellular region to promote cancer cell proliferation; bacterial riboflavin from Bacteroides cellulosilyticus inhibits CERS3 activity, reducing C26 ceramide and delaying colorectal cancer progression; aclidinium bromide also inhibits CERS3 activity.\",\n      \"method\": \"CERS3 overexpression/knockdown in CRC cells, EGFR binding assay, ceramide mass spectrometry, riboflavin-CERS3 activity inhibition assay, aclidinium bromide CERS3 activity assay, mouse CRC models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic inhibition assay, direct EGFR binding by ceramide product, multiple genetic and pharmacological approaches with in vivo validation\",\n      \"pmids\": [\"40609532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CerS3 (mammalian) expressed in yeast supports near-normal nutrient-dependent cell size modulation through production of C24–C26 ceramides, demonstrating that CERS3 substrate specificity for very-long-chain ceramides determines downstream TORC2 signaling and cell size control.\",\n      \"method\": \"Expression of mammalian CerS3 in yeast elongation mutants (elo3Δ), TORC2 signaling readout (Ypk1/2 pT662), cell size measurement under nutrient deprivation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in yeast with functional readout, but preprint and uses heterologous system\",\n      \"pmids\": [\"bio_10.1101_2025.11.28.691118\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Inducible knockdown of CerS3 in 3D human skin equivalents reduces polar lipid staining and causes a specific reduction in ultra-long-chain ceramide classes and chain lengths without disrupting stratification or terminal differentiation, confirming CerS3's specific role in ultra-long-chain ceramide synthesis for epidermal barrier lipid composition.\",\n      \"method\": \"Doxycycline-inducible shRNA knockdown of CerS3 in N/TERT keratinocytes in 3D HSEs, mass spectrometry lipidomics, Nile Red staining\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean inducible KD with lipidomic readout in 3D skin model, but preprint\",\n      \"pmids\": [\"bio_10.1101_2025.01.20.633956\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CerS3 overexpression promotes HCC cell proliferation, migration, and invasion via activation of the SMAD6 gene, as determined by RNA sequencing of downstream targets.\",\n      \"method\": \"Retroviral overexpression and lentiviral shRNA knockdown of CerS3 in HCC cell lines (Hep3B, HCCLM3), MTT/EdU proliferation assays, Transwell invasion assay, RNA sequencing\",\n      \"journal\": \"Zhong nan da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression/KD with downstream transcriptomic analysis but no direct biochemical link established\",\n      \"pmids\": [\"35753729\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CERS3 is a ceramide synthase that catalyzes the amide-bond formation between a long-chain sphingoid base and ultra-long-chain fatty acyl-CoAs (C26–C36, produced upstream by ELOVL1/ELOVL4), generating very-long-chain and acylceramides essential for epidermal permeability barrier formation and male germ cell meiosis; its activity is stimulated by ACBP (which delivers very-long-chain acyl-CoA substrates) and is regulated by CK2-mediated phosphorylation of its C-terminal region, while its transcription is controlled by PPARβ/δ during keratinocyte differentiation and repressed by nuclear CerS6 in endothelial cells downstream of S1PR1 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CERS3 is a ceramide synthase that catalyzes amide-bond formation between long-chain sphingoid bases and very-long-chain to ultra-long-chain fatty acyl-CoAs (C24–C36), generating the very-long-chain ceramides and acylceramide precursors essential for epidermal permeability barrier formation and male germ cell meiosis [PMID:16753040, PMID:23549421, PMID:26045466, PMID:28966260]. In the epidermis, CERS3 operates downstream of ELOVL1/ELOVL4-mediated fatty acid elongation and upstream of PNPLA1-catalyzed acylceramide completion; its transcription is induced by PPARβ/δ during keratinocyte differentiation, and its enzymatic activity is stimulated ~7-fold by acyl-CoA-binding protein (ACBP) and modestly regulated by CK2-mediated C-terminal phosphorylation [PMID:23826266, PMID:23689133, PMID:28320857, PMID:26887952]. Loss-of-function mutations in CERS3 cause autosomal recessive congenital ichthyosis (ARCI) through specific depletion of ultra-long-chain and acylceramides in the stratum corneum [PMID:23549421, PMID:23754960, PMID:33492757]. CERS3-produced C26 ceramide can also activate EGFR signaling to promote colorectal cancer cell proliferation, a pathway inhibitable by bacterial riboflavin or aclidinium bromide [PMID:40609532].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing CERS3 as a bona fide ceramide synthase with relatively broad acyl-CoA specificity (C16–C26) resolved the question of whether this uncharacterized LASS family member possessed intrinsic (dihydro)ceramide synthase activity.\",\n      \"evidence\": \"In vivo [³H]dihydrosphingosine labeling and in vitro ceramide synthase assay upon overexpression\",\n      \"pmids\": [\"16753040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preferred substrates in native tissues not yet defined\", \"No structural basis for substrate recognition\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of CERS3 as the dominant ceramide synthase in both testicular germ cells and differentiating keratinocytes established its tissue-specific roles in generating VLC-PUFA sphingolipids for spermatogenesis and 2-hydroxy-ceramides for epidermis.\",\n      \"evidence\": \"qRT-PCR expression profiling in testis and keratinocytes; lipidomic analysis of spermatogenic mutants; in vitro assays with 2-hydroxy-fatty acyl-CoA substrates\",\n      \"pmids\": [\"18308723\", \"18541923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genetic proof of CERS3 requirement in each tissue not yet available\", \"Mechanism by which CERS3 accommodates 2-hydroxy substrates unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that homozygous loss-of-function CERS3 mutations cause autosomal recessive congenital ichthyosis (ARCI) through depletion of C26–C34 ceramides proved CERS3 is essential for epidermal barrier function and positioned it in a defined biosynthetic pathway with ELOVL1 and PPARβ/δ.\",\n      \"evidence\": \"Exome sequencing of ARCI families, in vitro enzymatic assays of patient and recombinant mutant proteins, lipidomic profiling of patient keratinocytes, ELOVL1-KO mouse epistasis, PPARβ/δ regulation by siRNA and expression analysis\",\n      \"pmids\": [\"23549421\", \"23754960\", \"23826266\", \"23689133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter binding by PPARβ/δ not demonstrated\", \"Contribution of individual ultra-long-chain species to barrier function not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"CerS3-knockout mice revealed that CerS3 is required for meiotic progression and intercellular bridge stability in spermatocytes, confirming a cell-autonomous role in male fertility through production of sphingolipids with ultra-long polyunsaturated anchors.\",\n      \"evidence\": \"CerS3-KO mice with in situ mass spectrometric imaging and immunolocalization in pachytene spermatocytes and elongating spermatids\",\n      \"pmids\": [\"26045466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific sphingolipid species mediating intercellular bridge stability not identified\", \"Whether human male infertility results from CERS3 mutations is untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that CK2-mediated phosphorylation of the CERS3 C-terminal region modulates catalytic activity established a post-translational regulatory mechanism for this enzyme.\",\n      \"evidence\": \"CK2 inhibitor (CX-4945) treatment followed by in vitro ceramide synthase activity assay and phospho-mapping\",\n      \"pmids\": [\"26887952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Magnitude of regulation is modest; physiological contexts where this matters are unclear\", \"Individual phospho-site contributions not dissected by mutagenesis\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of ACBP as a physical interactor that delivers very-long-chain acyl-CoA to CerS3 and stimulates its activity ~7-fold resolved how substrate supply is coupled to ceramide synthesis, and placement of CERS3 within the complete acylceramide biosynthetic pathway (ELOVL1/4→CYP4F22→CERS3→PNPLA1) defined its precise enzymatic step.\",\n      \"evidence\": \"Co-immunoprecipitation of ACBP with CerS3, in vitro assays in ACBP-KO liver cytosol and testes lipidomics; biochemical pathway reconstitution\",\n      \"pmids\": [\"28320857\", \"28966260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ACBP–CerS3 interaction unknown\", \"Whether ACBP regulation is tissue-specific (skin vs. testis) not compared\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Quantitative enzymatic analysis of compound heterozygous CERS3 mutations demonstrated that reduction in acylceramide—not protein-bound ceramide—is sufficient to cause ichthyosis, refining the genotype-phenotype relationship.\",\n      \"evidence\": \"In vitro ceramide synthase assay of recombinant R75* and R229H mutant proteins with stratum corneum ceramide profiling by mass spectrometry\",\n      \"pmids\": [\"33492757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of residual activity needed to prevent disease not defined\", \"Whether modifier genes modulate phenotypic severity is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptional repression of CERS3 by nuclear CerS6 downstream of S1PR1 signaling in endothelial cells revealed an inter-CerS regulatory circuit linking sphingolipid metabolism to angiogenesis.\",\n      \"evidence\": \"siRNA knockdown and overexpression with nuclear fractionation in endothelial cells; in vitro and in vivo angiogenesis assays\",\n      \"pmids\": [\"36068200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CerS6 binding to CERS3 promoter not shown\", \"Not independently replicated\", \"Relevance to in vivo vascular biology beyond tumor angiogenesis untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that CERS3-produced C26 ceramide directly binds and activates EGFR to promote colorectal cancer cell proliferation, inhibitable by bacterial riboflavin or aclidinium bromide, extended CERS3 function to oncogenic signaling and identified the first pharmacological inhibitors of this enzyme.\",\n      \"evidence\": \"CERS3 overexpression/knockdown in CRC cells, EGFR extracellular domain binding assay, ceramide MS, riboflavin and aclidinium bromide inhibition assays, mouse CRC models\",\n      \"pmids\": [\"40609532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of CERS3 inhibitors over other CerS family members not characterized\", \"Whether C26 ceramide–EGFR binding occurs under physiological lipid concentrations is uncertain\", \"Structural mechanism of EGFR activation by C26 ceramide unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the three-dimensional structure of CERS3, the molecular basis of its ultra-long-chain acyl-CoA selectivity, the full scope of post-translational regulatory mechanisms, and whether CERS3 inhibition is therapeutically viable in cancer without compromising skin or testicular barrier function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure available\", \"Mechanism of acyl-chain length selectivity unresolved\", \"Therapeutic window for CERS3 inhibition not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 8, 9, 11, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 6, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACBP\",\n      \"ELOVL1\",\n      \"ELOVL4\",\n      \"CYP4F22\",\n      \"PNPLA1\",\n      \"CERS6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}