{"gene":"CERS3","run_date":"2026-06-09T22:57:18","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; overproduction in vivo increases several ceramide species, confirmed by [3H]dihydrosphingosine labelling, ESI-MS, and an in vitro ceramide synthase assay.","method":"In vivo [3H]dihydrosphingosine labelling, electrospray-ionization MS, in vitro (dihydro)ceramide synthase assay with overexpressed protein","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay combined with in vivo metabolic labelling and MS, replicated across two isoforms in same study","pmids":["16753040"],"is_preprint":false},{"year":2008,"finding":"CerS3 is the ceramide synthase responsible for synthesis of very long-chain polyunsaturated fatty acid (VLC-PUFA, C26–C32) sphingolipids in male germ cells; Cers3 mRNA is up-regulated >700-fold during postnatal testicular maturation and is restricted to germ cells among the six CERS family members.","method":"Quantitative RT-PCR during postnatal development, lipid analysis of testicular cell fractions, comparison with male sterile mouse mutants arrested at different spermatogenic stages","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (qPCR, lipidomics, genetic mutant models) in same study; finding replicated in later work","pmids":["18308723"],"is_preprint":false},{"year":2008,"finding":"All six CerS family members, including CerS3, can synthesize 2-hydroxy-ceramide when overproduced in HEK 293T cells, and produce 2-hydroxy-CER with acyl-chain length matching the respective non-hydroxy-CER produced; CerS3 mRNA is the most predominantly expressed in keratinocytes and is upregulated upon differentiation.","method":"Overexpression in HEK 293T cells, lipid analysis (in vivo and in vitro CerS assay), siRNA knockdown, quantitative RT-PCR in keratinocytes","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay, siRNA knockdown, and expression analysis; multiple orthogonal methods in single study","pmids":["18541923"],"is_preprint":false},{"year":2013,"finding":"A homozygous missense mutation in CERS3 inactivates ceramide synthase 3 activity (demonstrated by N-acylation assay with C26-CoA) in patient keratinocytes and recombinant mutant proteins, causing a specific loss of very long-chain ceramides (C26–C34) in terminally differentiating keratinocytes and impairing epidermal barrier function.","method":"Autozygosity mapping, exome sequencing, ceramide synthase activity assay (N-acylation with C26-CoA) in patient keratinocytes and recombinant proteins, lipidomics, reconstructed patient skin","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — loss-of-function mutation validated by enzymatic assay in both patient cells and recombinant protein, combined with lipidomics and skin reconstruction","pmids":["23549421"],"is_preprint":false},{"year":2013,"finding":"Splice site and deletion mutations in CERS3 cause disturbed sphingolipid profiles with reduced very long-chain ceramides, interfering with epidermal differentiation and demonstrating that CERS3 is essential for human epidermal lipid homeostasis.","method":"Genome-wide SNP genotyping, exome sequencing, functional analysis of patient skin and in vitro differentiated keratinocytes (sphingolipid profiling)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and functional data from patient skin and keratinocytes across multiple families; independently corroborates PMID 23549421","pmids":["23754960"],"is_preprint":false},{"year":2013,"finding":"CERS3 and ELOVL4 are co-regulated at both transcriptional and enzymatic levels during keratinocyte differentiation; knockdown of CERS3 reduces elongase activities toward ULC acyl-CoAs, indicating CERS3 positively regulates ultra-long-chain fatty acid (ULCFA) synthesis. PPARβ/δ is involved in transcriptional up-regulation of both genes.","method":"siRNA knockdown of CERS3 in keratinocytes with measurement of elongase activity, qRT-PCR, in vivo and in vitro expression analyses, PPARβ/δ pathway analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific enzymatic readout, expression analysis, PPARβ/δ inhibitor experiments; multiple methods in one study","pmids":["23826266"],"is_preprint":false},{"year":2013,"finding":"Two ceramide synthases, CerS2 and CerS3, expressed in an epidermal-layer-specific manner, regulate ELOVL1 to produce acyl-CoAs with different chain lengths; loss of Elovl1 in mice decreases ceramides with ≥C26 fatty acids (CerS3 substrates) while increasing those with ≤C24, establishing a cooperative pathway for epidermal ceramide chain-length determination.","method":"Elovl1 knockout mice, lipid mass spectrometry of epidermis, layer-specific expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with comprehensive lipidomics; pathway placement of CerS3 in epidermal VLCFA ceramide synthesis confirmed","pmids":["23689133"],"is_preprint":false},{"year":2015,"finding":"CerS3 localizes in pachytene spermatocytes until completion of meiosis and in elongating spermatids; CerS3-KO mice display enhanced apoptosis during meiosis, formation of multinuclear giant cells, and spermatogenic arrest, establishing that CerS3-derived ceramides with ultra-long polyunsaturated anchors are required for stability of intercellular bridges during male meiotic cytokinesis.","method":"High-resolution mass spectrometric imaging (in situ), CerS3 knockout mice, glucosylceramide synthase KO mice (genetic epistasis), immunolocalization of CerS3","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CerS3-KO with defined cellular phenotype, in situ MS imaging, genetic epistasis with GlcCer synthase KO; replicated and extended earlier findings","pmids":["26045466"],"is_preprint":false},{"year":2016,"finding":"CERS3 (along with CERS2, 4, 5, 6) is phosphorylated at the cytoplasmic C-terminal region, predominantly at CK2 consensus motifs; phosphorylation modestly increases CerS3 catalytic activity (Vmax), as shown by dephosphorylation experiments reducing activity.","method":"Phosphorylation mapping by MS, CK2 inhibitor (CX-4945) treatment, in vitro ceramide synthase activity assays before and after dephosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic activity assays combined with specific kinase inhibitor and phosphorylation mapping; applied to multiple CERS members including CERS3","pmids":["26887952"],"is_preprint":false},{"year":2017,"finding":"Acyl-CoA-binding protein (ACBP) stimulates CerS3 activity approximately 7-fold in vitro, physically interacts with CerS3 (Co-IP), and requires binding of very-long-chain acyl-CoA esters for this stimulatory effect; CerS3 activity and very-long-chain ceramide levels are significantly reduced in testes of ACBP-knockout mice.","method":"In vitro ceramide synthase activity assay with ACBP, Co-immunoprecipitation of ACBP with CerS3, ACBP-KO mouse testes lipidomics, cytosol complementation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, reciprocal Co-IP, and genetic KO model with lipidomics; multiple orthogonal methods","pmids":["28320857"],"is_preprint":false},{"year":2017,"finding":"In the acylceramide biosynthetic pathway, CerS3 performs amide-bond formation between a sphingoid long-chain base and an ultra-long-chain fatty acid (ULCFA, 28–36 carbons) that has been ω-hydroxylated by CYP4F22, and the resulting ω-hydroxyceramide is then transacylated by PNPLA1 to generate acylceramide.","method":"Pathway reconstitution and mutant analysis using CYP4F22 and PNPLA1 mutants demonstrating placement of CerS3 in the sequential pathway","journal":"Yakugaku zasshi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement supported by functional mutation studies in companion papers; this review/summary paper cites the experimental evidence from multiple studies","pmids":["28966260"],"is_preprint":false},{"year":2021,"finding":"In a patient with compound heterozygous CERS3 mutations (p.Arg75* and p.Arg229His), ceramide synthase activity was reduced to 4% and 56% of wild-type respectively; stratum corneum ceramide profiling showed greatly reduced acylceramide levels but nearly unchanged protein-bound ceramide levels, indicating acylceramide reduction alone is sufficient to cause ichthyosis.","method":"In vitro ceramide synthase activity assay with recombinant mutant CERS3 proteins, comprehensive stratum corneum ceramide profiling by LC-MS/MS","journal":"The Journal of dermatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant mutant protein activity assay plus comprehensive lipidomics in patient SC; multiple orthogonal methods in single study","pmids":["33492757"],"is_preprint":false},{"year":2022,"finding":"S1PR1 downregulates CERS3 transcription in endothelial cells by inducing CerS6 nuclear translocation, which inhibits CERS3 at the transcriptional level, thereby decreasing ceramide levels and promoting angiogenesis in hepatocellular carcinoma.","method":"S1PR1 overexpression/knockdown in endothelial cells, CerS6 nuclear translocation imaging, qRT-PCR of CERS3, ceramide quantification, in vitro and in vivo angiogenesis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, CerS6 nuclear translocation linked to CERS3 transcriptional repression, but mechanism of CerS6 acting as transcriptional repressor not biochemically reconstituted","pmids":["36068200"],"is_preprint":false},{"year":2022,"finding":"CerS3 knockdown in an in vitro Plasmodium berghei liver stage model reduced parasitophorous vacuole size and infection rate (but not invasion), establishing that host CerS3-derived ceramides support parasite development within hepatocytes.","method":"siRNA-mediated knockdown of CERS3 in hepatocytes, P. berghei liver stage infection assay with measurement of PV size and infection rate","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KD with specific phenotypic readout (PV size, infection rate), single lab, single method","pmids":["40689642"],"is_preprint":false},{"year":2022,"finding":"CERS3 knockdown in Hep3B hepatocellular carcinoma cells (and overexpression in HCCLM3 cells) alters cell proliferation, migration, and invasion; RNA sequencing identified SMAD6 as a downstream effector of CerS3 in HCC cells.","method":"Retroviral/lentiviral overexpression and shRNA knockdown, MTT, EdU, Transwell, scratch assays, RNA sequencing","journal":"Zhong nan da xue xue bao","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phenotypic assays with transcriptomic inference; SMAD6 as downstream target is RNA-seq based without biochemical validation of the mechanism","pmids":["35753729"],"is_preprint":false},{"year":2025,"finding":"Riboflavin produced by Bacteroides cellulosilyticus directly inhibits CERS3 enzymatic activity, reducing d18:1/26:0 ceramide (C26) levels in colorectal cancer; C26 ceramide activates EGFR by binding its extracellular region, promoting cancer cell proliferation; aclidinium bromide also inhibits CERS3 activity.","method":"CERS3 activity assays with riboflavin and aclidinium bromide, ceramide profiling in CRC patients and mouse models, EGFR binding assays, bacterial supplementation experiments","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic inhibition assay, EGFR binding, patient and mouse model lipidomics, microbial supplementation; multiple orthogonal methods in single study","pmids":["40609532"],"is_preprint":false},{"year":2025,"finding":"siRNA-mediated knockdown of CERS3 in sheep embryos resulted in a 9.5% decrease in blastocyst formation rate, indicating a functional role for CERS3 in early embryonic development.","method":"siRNA knockdown in sheep embryos, blastocyst formation rate assessment","journal":"Epigenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA KD) in a non-canonical model (sheep embryo), phenotype is blastocyst rate without molecular mechanism","pmids":["41024457"],"is_preprint":false},{"year":2025,"finding":"In a human skin equivalent model, doxycycline-inducible shRNA knockdown of CerS3 reduces polar lipid staining (Nile Red) and causes a significant reduction in specific ceramide classes and ceramide chain length, without affecting stratification or terminal differentiation; the knockdown is reversible upon doxycycline removal.","method":"Inducible shRNA in 3D human skin equivalents (HSEs), Nile Red staining, mass spectrometry-based lipidomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean inducible KD with defined lipidomic readout in 3D HSE model; single lab preprint","pmids":[],"is_preprint":true}],"current_model":"CERS3 (CerS3) is a (dihydro)ceramide synthase that preferentially synthesizes ceramides containing very long-chain fatty acids (≥C26), is activated by phosphorylation in its C-terminal region by casein kinase 2, is stimulated by direct interaction with acyl-CoA-binding protein (ACBP), and is transcriptionally regulated by PPARβ/δ during keratinocyte differentiation; it is essential for epidermal barrier formation (by catalyzing the amide-bond step in acylceramide biosynthesis downstream of ELOVL4 and CYP4F22 and upstream of PNPLA1), for male meiotic cytokinesis through synthesis of ultra-long polyunsaturated ceramide anchors required for intercellular bridge stability, and its enzymatic activity can be inhibited by riboflavin and aclidinium bromide; mutations inactivating its activity cause autosomal recessive congenital ichthyosis with loss of very long-chain stratum corneum ceramides."},"narrative":{"mechanistic_narrative":"CERS3 (CerS3/LASS3) is a (dihydro)ceramide synthase that catalyzes amide-bond formation between a sphingoid long-chain base and a fatty acyl-CoA, with a distinctive preference for very-long- and ultra-long-chain (≥C26, up to C32–C36) acyl chains [PMID:16753040, PMID:23549421, PMID:28966260]. Through this activity it is the principal source of very-long-chain ceramides in two specialized tissues: the differentiating epidermis, where it is the predominant CerS isoform and is induced upon keratinocyte differentiation [PMID:18541923], and the male germ line, where it is restricted to germ cells and sharply upregulated during testicular maturation [PMID:18308723]. In skin, CERS3 operates within the acylceramide pathway, acting downstream of the ELOVL1/ELOVL4 elongation machinery and CYP4F22-mediated ω-hydroxylation to generate ω-hydroxyceramides that are subsequently transacylated by PNPLA1 [PMID:23826266, PMID:23689133, PMID:28966260]; it is co-regulated with ELOVL4 by PPARβ/δ during differentiation and itself positively feeds back on ultra-long-chain fatty acid synthesis [PMID:23826266]. In spermatogenesis, CerS3-derived ultra-long polyunsaturated ceramide anchors are required for intercellular bridge stability, and its loss causes apoptosis, multinuclear giant cell formation, and meiotic arrest [PMID:26045466]. Its catalytic activity is tuned by C-terminal CK2-site phosphorylation, which increases Vmax [PMID:26887952], and is stimulated several-fold by physical interaction with acyl-CoA-binding protein (ACBP), which delivers very-long-chain acyl-CoA substrates [PMID:28320857]. Enzymatic inactivation of CERS3 by recessive mutations causes autosomal recessive congenital ichthyosis through loss of very-long-chain stratum corneum ceramides, with reduction of acylceramide alone being sufficient for the phenotype [PMID:23549421, PMID:23754960, PMID:33492757]. CERS3 activity is directly inhibited by riboflavin and by aclidinium bromide, linking its C26 ceramide product to EGFR activation in colorectal cancer [PMID:40609532].","teleology":[{"year":2006,"claim":"Established that CERS3 is a catalytically active (dihydro)ceramide synthase, defining its core biochemical activity before any tissue role was known.","evidence":"In vivo [3H]dihydrosphingosine labelling, ESI-MS, and in vitro CerS assay with overexpressed protein","pmids":["16753040"],"confidence":"High","gaps":["Initial broad substrate report did not resolve the very-long-chain preference later defined","No physiological tissue context established"]},{"year":2008,"claim":"Identified the two specialized tissues where CERS3 dominates — germ cells and keratinocytes — and linked it to very-long-chain/polyunsaturated sphingolipid production.","evidence":"qRT-PCR across postnatal testis development and keratinocyte differentiation, lipidomics of cell fractions, comparison with spermatogenic mutants","pmids":["18308723","18541923"],"confidence":"High","gaps":["Did not establish whether VLC ceramide loss is causal for any phenotype","Mechanism of acyl-chain-length selectivity unresolved"]},{"year":2013,"claim":"Demonstrated that loss-of-function CERS3 mutations cause autosomal recessive congenital ichthyosis through specific depletion of very-long-chain ceramides, connecting enzyme activity to human barrier disease.","evidence":"Autozygosity mapping/exome sequencing, N-acylation enzymatic assays in patient keratinocytes and recombinant mutants, lipidomics, reconstructed skin across families","pmids":["23549421","23754960"],"confidence":"High","gaps":["Which downstream lipid species (acylceramide vs protein-bound) is most critical not yet resolved","Did not place CERS3 within the full enzymatic pathway"]},{"year":2013,"claim":"Placed CERS3 in a cooperative epidermal chain-elongation pathway with ELOVL1/ELOVL4 under PPARβ/δ control, showing it both consumes and promotes ultra-long-chain acyl-CoA synthesis.","evidence":"Elovl1-KO mouse epidermal lipidomics, CERS3 siRNA knockdown with elongase activity readout, PPARβ/δ pathway analysis","pmids":["23689133","23826266"],"confidence":"High","gaps":["Molecular basis of CERS3-elongase co-regulation not defined","Direct PPARβ/δ binding to the CERS3 locus not shown"]},{"year":2015,"claim":"Defined the germ-cell function of CerS3: its ultra-long polyunsaturated ceramides stabilize intercellular bridges required for male meiotic cytokinesis.","evidence":"CerS3-KO mice with apoptosis/multinuclear giant cell/meiotic-arrest phenotype, in situ MS imaging, genetic epistasis with glucosylceramide synthase KO","pmids":["26045466"],"confidence":"High","gaps":["Molecular mechanism by which ceramide anchors stabilize bridges not detailed","Lipid-protein interactions at the bridge undefined"]},{"year":2017,"claim":"Identified two regulatory inputs to CERS3 activity — CK2-site phosphorylation and ACBP-mediated substrate delivery — explaining how very-long-chain acyl-CoA usage is enabled and tuned.","evidence":"Phospho-mapping with CK2 inhibitor and dephosphorylation assays; in vitro reconstitution, reciprocal Co-IP, and ACBP-KO testis lipidomics","pmids":["26887952","28320857"],"confidence":"High","gaps":["Physiological conditions controlling CK2 phosphorylation of CERS3 unknown","Structural basis of ACBP–CerS3 interaction not resolved"]},{"year":2017,"claim":"Positioned CERS3 within the sequential acylceramide pathway as the amide-bond-forming step between CYP4F22-derived ω-hydroxy ULCFA and PNPLA1 transacylation.","evidence":"Pathway summary integrating CYP4F22 and PNPLA1 mutant analyses","pmids":["28966260"],"confidence":"Medium","gaps":["Review-level synthesis rather than single reconstituted assay","Order/coupling of ω-hydroxylation and N-acylation not biochemically isolated"]},{"year":2021,"claim":"Refined the disease mechanism by showing that reduction of acylceramide alone, with near-normal protein-bound ceramide, is sufficient to cause ichthyosis.","evidence":"Recombinant mutant CERS3 activity assays plus comprehensive stratum corneum ceramide profiling by LC-MS/MS in a compound-heterozygous patient","pmids":["33492757"],"confidence":"High","gaps":["Genotype–residual-activity–severity relationship across more patients not mapped","Single patient lipidomic comparison"]},{"year":2022,"claim":"Extended CERS3 biology beyond barrier/germline into context-dependent transcriptional regulation and roles in cancer and host–pathogen interactions.","evidence":"S1PR1/CerS6 nuclear-translocation studies in endothelial cells; CERS3 knockdown/overexpression in HCC cells with RNA-seq; CERS3 siRNA in P. berghei liver-stage hepatocyte model","pmids":["36068200","35753729","40689642"],"confidence":"Medium","gaps":["CerS6-mediated transcriptional repression of CERS3 not biochemically reconstituted","SMAD6 link is RNA-seq inference without mechanistic validation","Parasite phenotype from single method/lab"]},{"year":2025,"claim":"Identified small-molecule and microbial inhibitors of CERS3 and linked its C26 ceramide product to oncogenic EGFR signaling.","evidence":"CERS3 activity assays with riboflavin and aclidinium bromide, EGFR binding assays, CRC patient/mouse lipidomics, bacterial supplementation","pmids":["40609532"],"confidence":"High","gaps":["Structural basis of riboflavin/aclidinium inhibition of CERS3 not defined","Generality of C26-ceramide/EGFR axis beyond CRC unknown"]},{"year":null,"claim":"How CERS3 acyl-chain selectivity, phosphoregulation, and ACBP-mediated substrate channeling are structurally integrated, and how its product ceramides are sensed by downstream effectors, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CERS3 or its substrate-binding pocket in the corpus","Mechanism coupling phosphorylation, ACBP binding, and catalysis undefined","Direct chromatin-level transcriptional regulators not biochemically established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,9,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["ACBP","ELOVL4","ELOVL1","CYP4F22","PNPLA1","CK2"],"other_free_text":[]}},"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":158,"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":145,"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":135,"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":132,"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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overproduction in vivo increases several ceramide species, confirmed by [3H]dihydrosphingosine labelling, ESI-MS, and an in vitro ceramide synthase assay.\",\n      \"method\": \"In vivo [3H]dihydrosphingosine labelling, electrospray-ionization MS, in vitro (dihydro)ceramide synthase assay with overexpressed protein\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay combined with in vivo metabolic labelling and MS, replicated across two isoforms in same study\",\n      \"pmids\": [\"16753040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CerS3 is the ceramide synthase responsible for synthesis of very long-chain polyunsaturated fatty acid (VLC-PUFA, C26–C32) sphingolipids in male germ cells; Cers3 mRNA is up-regulated >700-fold during postnatal testicular maturation and is restricted to germ cells among the six CERS family members.\",\n      \"method\": \"Quantitative RT-PCR during postnatal development, lipid analysis of testicular cell fractions, comparison with male sterile mouse mutants arrested at different spermatogenic stages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (qPCR, lipidomics, genetic mutant models) in same study; finding replicated in later work\",\n      \"pmids\": [\"18308723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"All six CerS family members, including CerS3, can synthesize 2-hydroxy-ceramide when overproduced in HEK 293T cells, and produce 2-hydroxy-CER with acyl-chain length matching the respective non-hydroxy-CER produced; CerS3 mRNA is the most predominantly expressed in keratinocytes and is upregulated upon differentiation.\",\n      \"method\": \"Overexpression in HEK 293T cells, lipid analysis (in vivo and in vitro CerS assay), siRNA knockdown, quantitative RT-PCR in keratinocytes\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay, siRNA knockdown, and expression analysis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"18541923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A homozygous missense mutation in CERS3 inactivates ceramide synthase 3 activity (demonstrated by N-acylation assay with C26-CoA) in patient keratinocytes and recombinant mutant proteins, causing a specific loss of very long-chain ceramides (C26–C34) in terminally differentiating keratinocytes and impairing epidermal barrier function.\",\n      \"method\": \"Autozygosity mapping, exome sequencing, ceramide synthase activity assay (N-acylation with C26-CoA) in patient keratinocytes and recombinant proteins, lipidomics, reconstructed patient skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — loss-of-function mutation validated by enzymatic assay in both patient cells and recombinant protein, combined with lipidomics and skin reconstruction\",\n      \"pmids\": [\"23549421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Splice site and deletion mutations in CERS3 cause disturbed sphingolipid profiles with reduced very long-chain ceramides, interfering with epidermal differentiation and demonstrating that CERS3 is essential for human epidermal lipid homeostasis.\",\n      \"method\": \"Genome-wide SNP genotyping, exome sequencing, functional analysis of patient skin and in vitro differentiated keratinocytes (sphingolipid profiling)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and functional data from patient skin and keratinocytes across multiple families; independently corroborates PMID 23549421\",\n      \"pmids\": [\"23754960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CERS3 and ELOVL4 are co-regulated at both transcriptional and enzymatic levels during keratinocyte differentiation; knockdown of CERS3 reduces elongase activities toward ULC acyl-CoAs, indicating CERS3 positively regulates ultra-long-chain fatty acid (ULCFA) synthesis. PPARβ/δ is involved in transcriptional up-regulation of both genes.\",\n      \"method\": \"siRNA knockdown of CERS3 in keratinocytes with measurement of elongase activity, qRT-PCR, in vivo and in vitro expression analyses, PPARβ/δ pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific enzymatic readout, expression analysis, PPARβ/δ inhibitor experiments; multiple methods in one study\",\n      \"pmids\": [\"23826266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two ceramide synthases, CerS2 and CerS3, expressed in an epidermal-layer-specific manner, regulate ELOVL1 to produce acyl-CoAs with different chain lengths; loss of Elovl1 in mice decreases ceramides with ≥C26 fatty acids (CerS3 substrates) while increasing those with ≤C24, establishing a cooperative pathway for epidermal ceramide chain-length determination.\",\n      \"method\": \"Elovl1 knockout mice, lipid mass spectrometry of epidermis, layer-specific expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with comprehensive lipidomics; pathway placement of CerS3 in epidermal VLCFA ceramide synthesis confirmed\",\n      \"pmids\": [\"23689133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CerS3 localizes in pachytene spermatocytes until completion of meiosis and in elongating spermatids; CerS3-KO mice display enhanced apoptosis during meiosis, formation of multinuclear giant cells, and spermatogenic arrest, establishing that CerS3-derived ceramides with ultra-long polyunsaturated anchors are required for stability of intercellular bridges during male meiotic cytokinesis.\",\n      \"method\": \"High-resolution mass spectrometric imaging (in situ), CerS3 knockout mice, glucosylceramide synthase KO mice (genetic epistasis), immunolocalization of CerS3\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CerS3-KO with defined cellular phenotype, in situ MS imaging, genetic epistasis with GlcCer synthase KO; replicated and extended earlier findings\",\n      \"pmids\": [\"26045466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CERS3 (along with CERS2, 4, 5, 6) is phosphorylated at the cytoplasmic C-terminal region, predominantly at CK2 consensus motifs; phosphorylation modestly increases CerS3 catalytic activity (Vmax), as shown by dephosphorylation experiments reducing activity.\",\n      \"method\": \"Phosphorylation mapping by MS, CK2 inhibitor (CX-4945) treatment, in vitro ceramide synthase activity assays before and after dephosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic activity assays combined with specific kinase inhibitor and phosphorylation mapping; applied to multiple CERS members including CERS3\",\n      \"pmids\": [\"26887952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Acyl-CoA-binding protein (ACBP) stimulates CerS3 activity approximately 7-fold in vitro, physically interacts with CerS3 (Co-IP), and requires binding of very-long-chain acyl-CoA esters for this stimulatory effect; CerS3 activity and very-long-chain ceramide levels are significantly reduced in testes of ACBP-knockout mice.\",\n      \"method\": \"In vitro ceramide synthase activity assay with ACBP, Co-immunoprecipitation of ACBP with CerS3, ACBP-KO mouse testes lipidomics, cytosol complementation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, reciprocal Co-IP, and genetic KO model with lipidomics; multiple orthogonal methods\",\n      \"pmids\": [\"28320857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the acylceramide biosynthetic pathway, CerS3 performs amide-bond formation between a sphingoid long-chain base and an ultra-long-chain fatty acid (ULCFA, 28–36 carbons) that has been ω-hydroxylated by CYP4F22, and the resulting ω-hydroxyceramide is then transacylated by PNPLA1 to generate acylceramide.\",\n      \"method\": \"Pathway reconstitution and mutant analysis using CYP4F22 and PNPLA1 mutants demonstrating placement of CerS3 in the sequential pathway\",\n      \"journal\": \"Yakugaku zasshi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement supported by functional mutation studies in companion papers; this review/summary paper cites the experimental evidence from multiple studies\",\n      \"pmids\": [\"28966260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In a patient with compound heterozygous CERS3 mutations (p.Arg75* and p.Arg229His), ceramide synthase activity was reduced to 4% and 56% of wild-type respectively; stratum corneum ceramide profiling showed greatly reduced acylceramide levels but nearly unchanged protein-bound ceramide levels, indicating acylceramide reduction alone is sufficient to cause ichthyosis.\",\n      \"method\": \"In vitro ceramide synthase activity assay with recombinant mutant CERS3 proteins, comprehensive stratum corneum ceramide profiling by LC-MS/MS\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant mutant protein activity assay plus comprehensive lipidomics in patient SC; multiple orthogonal methods in single study\",\n      \"pmids\": [\"33492757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S1PR1 downregulates CERS3 transcription in endothelial cells by inducing CerS6 nuclear translocation, which inhibits CERS3 at the transcriptional level, thereby decreasing ceramide levels and promoting angiogenesis in hepatocellular carcinoma.\",\n      \"method\": \"S1PR1 overexpression/knockdown in endothelial cells, CerS6 nuclear translocation imaging, qRT-PCR of CERS3, ceramide quantification, in vitro and in vivo angiogenesis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, CerS6 nuclear translocation linked to CERS3 transcriptional repression, but mechanism of CerS6 acting as transcriptional repressor not biochemically reconstituted\",\n      \"pmids\": [\"36068200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CerS3 knockdown in an in vitro Plasmodium berghei liver stage model reduced parasitophorous vacuole size and infection rate (but not invasion), establishing that host CerS3-derived ceramides support parasite development within hepatocytes.\",\n      \"method\": \"siRNA-mediated knockdown of CERS3 in hepatocytes, P. berghei liver stage infection assay with measurement of PV size and infection rate\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KD with specific phenotypic readout (PV size, infection rate), single lab, single method\",\n      \"pmids\": [\"40689642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CERS3 knockdown in Hep3B hepatocellular carcinoma cells (and overexpression in HCCLM3 cells) alters cell proliferation, migration, and invasion; RNA sequencing identified SMAD6 as a downstream effector of CerS3 in HCC cells.\",\n      \"method\": \"Retroviral/lentiviral overexpression and shRNA knockdown, MTT, EdU, Transwell, scratch assays, RNA sequencing\",\n      \"journal\": \"Zhong nan da xue xue bao\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phenotypic assays with transcriptomic inference; SMAD6 as downstream target is RNA-seq based without biochemical validation of the mechanism\",\n      \"pmids\": [\"35753729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Riboflavin produced by Bacteroides cellulosilyticus directly inhibits CERS3 enzymatic activity, reducing d18:1/26:0 ceramide (C26) levels in colorectal cancer; C26 ceramide activates EGFR by binding its extracellular region, promoting cancer cell proliferation; aclidinium bromide also inhibits CERS3 activity.\",\n      \"method\": \"CERS3 activity assays with riboflavin and aclidinium bromide, ceramide profiling in CRC patients and mouse models, EGFR binding assays, bacterial supplementation experiments\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic inhibition assay, EGFR binding, patient and mouse model lipidomics, microbial supplementation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"40609532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"siRNA-mediated knockdown of CERS3 in sheep embryos resulted in a 9.5% decrease in blastocyst formation rate, indicating a functional role for CERS3 in early embryonic development.\",\n      \"method\": \"siRNA knockdown in sheep embryos, blastocyst formation rate assessment\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA KD) in a non-canonical model (sheep embryo), phenotype is blastocyst rate without molecular mechanism\",\n      \"pmids\": [\"41024457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a human skin equivalent model, doxycycline-inducible shRNA knockdown of CerS3 reduces polar lipid staining (Nile Red) and causes a significant reduction in specific ceramide classes and ceramide chain length, without affecting stratification or terminal differentiation; the knockdown is reversible upon doxycycline removal.\",\n      \"method\": \"Inducible shRNA in 3D human skin equivalents (HSEs), Nile Red staining, mass spectrometry-based lipidomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean inducible KD with defined lipidomic readout in 3D HSE model; single lab preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CERS3 (CerS3) is a (dihydro)ceramide synthase that preferentially synthesizes ceramides containing very long-chain fatty acids (≥C26), is activated by phosphorylation in its C-terminal region by casein kinase 2, is stimulated by direct interaction with acyl-CoA-binding protein (ACBP), and is transcriptionally regulated by PPARβ/δ during keratinocyte differentiation; it is essential for epidermal barrier formation (by catalyzing the amide-bond step in acylceramide biosynthesis downstream of ELOVL4 and CYP4F22 and upstream of PNPLA1), for male meiotic cytokinesis through synthesis of ultra-long polyunsaturated ceramide anchors required for intercellular bridge stability, and its enzymatic activity can be inhibited by riboflavin and aclidinium bromide; mutations inactivating its activity cause autosomal recessive congenital ichthyosis with loss of very long-chain stratum corneum ceramides.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CERS3 (CerS3/LASS3) is a (dihydro)ceramide synthase that catalyzes amide-bond formation between a sphingoid long-chain base and a fatty acyl-CoA, with a distinctive preference for very-long- and ultra-long-chain (\\u2265C26, up to C32\\u2013C36) acyl chains [#0, #3, #10]. Through this activity it is the principal source of very-long-chain ceramides in two specialized tissues: the differentiating epidermis, where it is the predominant CerS isoform and is induced upon keratinocyte differentiation [#2], and the male germ line, where it is restricted to germ cells and sharply upregulated during testicular maturation [#1]. In skin, CERS3 operates within the acylceramide pathway, acting downstream of the ELOVL1/ELOVL4 elongation machinery and CYP4F22-mediated \\u03c9-hydroxylation to generate \\u03c9-hydroxyceramides that are subsequently transacylated by PNPLA1 [#5, #6, #10]; it is co-regulated with ELOVL4 by PPAR\\u03b2/\\u03b4 during differentiation and itself positively feeds back on ultra-long-chain fatty acid synthesis [#5]. In spermatogenesis, CerS3-derived ultra-long polyunsaturated ceramide anchors are required for intercellular bridge stability, and its loss causes apoptosis, multinuclear giant cell formation, and meiotic arrest [#7]. Its catalytic activity is tuned by C-terminal CK2-site phosphorylation, which increases Vmax [#8], and is stimulated several-fold by physical interaction with acyl-CoA-binding protein (ACBP), which delivers very-long-chain acyl-CoA substrates [#9]. Enzymatic inactivation of CERS3 by recessive mutations causes autosomal recessive congenital ichthyosis through loss of very-long-chain stratum corneum ceramides, with reduction of acylceramide alone being sufficient for the phenotype [#3, #4, #11]. CERS3 activity is directly inhibited by riboflavin and by aclidinium bromide, linking its C26 ceramide product to EGFR activation in colorectal cancer [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that CERS3 is a catalytically active (dihydro)ceramide synthase, defining its core biochemical activity before any tissue role was known.\",\n      \"evidence\": \"In vivo [3H]dihydrosphingosine labelling, ESI-MS, and in vitro CerS assay with overexpressed protein\",\n      \"pmids\": [\"16753040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initial broad substrate report did not resolve the very-long-chain preference later defined\", \"No physiological tissue context established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the two specialized tissues where CERS3 dominates \\u2014 germ cells and keratinocytes \\u2014 and linked it to very-long-chain/polyunsaturated sphingolipid production.\",\n      \"evidence\": \"qRT-PCR across postnatal testis development and keratinocyte differentiation, lipidomics of cell fractions, comparison with spermatogenic mutants\",\n      \"pmids\": [\"18308723\", \"18541923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether VLC ceramide loss is causal for any phenotype\", \"Mechanism of acyl-chain-length selectivity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that loss-of-function CERS3 mutations cause autosomal recessive congenital ichthyosis through specific depletion of very-long-chain ceramides, connecting enzyme activity to human barrier disease.\",\n      \"evidence\": \"Autozygosity mapping/exome sequencing, N-acylation enzymatic assays in patient keratinocytes and recombinant mutants, lipidomics, reconstructed skin across families\",\n      \"pmids\": [\"23549421\", \"23754960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream lipid species (acylceramide vs protein-bound) is most critical not yet resolved\", \"Did not place CERS3 within the full enzymatic pathway\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed CERS3 in a cooperative epidermal chain-elongation pathway with ELOVL1/ELOVL4 under PPAR\\u03b2/\\u03b4 control, showing it both consumes and promotes ultra-long-chain acyl-CoA synthesis.\",\n      \"evidence\": \"Elovl1-KO mouse epidermal lipidomics, CERS3 siRNA knockdown with elongase activity readout, PPAR\\u03b2/\\u03b4 pathway analysis\",\n      \"pmids\": [\"23689133\", \"23826266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CERS3-elongase co-regulation not defined\", \"Direct PPAR\\u03b2/\\u03b4 binding to the CERS3 locus not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the germ-cell function of CerS3: its ultra-long polyunsaturated ceramides stabilize intercellular bridges required for male meiotic cytokinesis.\",\n      \"evidence\": \"CerS3-KO mice with apoptosis/multinuclear giant cell/meiotic-arrest phenotype, in situ MS imaging, genetic epistasis with glucosylceramide synthase KO\",\n      \"pmids\": [\"26045466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which ceramide anchors stabilize bridges not detailed\", \"Lipid-protein interactions at the bridge undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified two regulatory inputs to CERS3 activity \\u2014 CK2-site phosphorylation and ACBP-mediated substrate delivery \\u2014 explaining how very-long-chain acyl-CoA usage is enabled and tuned.\",\n      \"evidence\": \"Phospho-mapping with CK2 inhibitor and dephosphorylation assays; in vitro reconstitution, reciprocal Co-IP, and ACBP-KO testis lipidomics\",\n      \"pmids\": [\"26887952\", \"28320857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions controlling CK2 phosphorylation of CERS3 unknown\", \"Structural basis of ACBP\\u2013CerS3 interaction not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Positioned CERS3 within the sequential acylceramide pathway as the amide-bond-forming step between CYP4F22-derived \\u03c9-hydroxy ULCFA and PNPLA1 transacylation.\",\n      \"evidence\": \"Pathway summary integrating CYP4F22 and PNPLA1 mutant analyses\",\n      \"pmids\": [\"28966260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review-level synthesis rather than single reconstituted assay\", \"Order/coupling of \\u03c9-hydroxylation and N-acylation not biochemically isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the disease mechanism by showing that reduction of acylceramide alone, with near-normal protein-bound ceramide, is sufficient to cause ichthyosis.\",\n      \"evidence\": \"Recombinant mutant CERS3 activity assays plus comprehensive stratum corneum ceramide profiling by LC-MS/MS in a compound-heterozygous patient\",\n      \"pmids\": [\"33492757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype\\u2013residual-activity\\u2013severity relationship across more patients not mapped\", \"Single patient lipidomic comparison\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended CERS3 biology beyond barrier/germline into context-dependent transcriptional regulation and roles in cancer and host\\u2013pathogen interactions.\",\n      \"evidence\": \"S1PR1/CerS6 nuclear-translocation studies in endothelial cells; CERS3 knockdown/overexpression in HCC cells with RNA-seq; CERS3 siRNA in P. berghei liver-stage hepatocyte model\",\n      \"pmids\": [\"36068200\", \"35753729\", \"40689642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CerS6-mediated transcriptional repression of CERS3 not biochemically reconstituted\", \"SMAD6 link is RNA-seq inference without mechanistic validation\", \"Parasite phenotype from single method/lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified small-molecule and microbial inhibitors of CERS3 and linked its C26 ceramide product to oncogenic EGFR signaling.\",\n      \"evidence\": \"CERS3 activity assays with riboflavin and aclidinium bromide, EGFR binding assays, CRC patient/mouse lipidomics, bacterial supplementation\",\n      \"pmids\": [\"40609532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of riboflavin/aclidinium inhibition of CERS3 not defined\", \"Generality of C26-ceramide/EGFR axis beyond CRC unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CERS3 acyl-chain selectivity, phosphoregulation, and ACBP-mediated substrate channeling are structurally integrated, and how its product ceramides are sensed by downstream effectors, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CERS3 or its substrate-binding pocket in the corpus\", \"Mechanism coupling phosphorylation, ACBP binding, and catalysis undefined\", \"Direct chromatin-level transcriptional regulators not biochemically established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 9, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACBP\",\n      \"ELOVL4\",\n      \"ELOVL1\",\n      \"CYP4F22\",\n      \"PNPLA1\",\n      \"CK2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}