{"gene":"ZDHHC8","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"ZDHHC8 encodes a putative transmembrane palmitoyltransferase; a SNP (rs175174) in intron 4 modulates retention of intron 4, regulating the level of the fully functional transcript. Zdhhc8-knockout mice show sexually dimorphic prepulse inhibition deficits and decreased sensitivity to MK801, implicating ZDHHC8-dependent palmitoylation of neuronal proteins in psychiatric phenotypes.","method":"SNP genotyping, splice analysis, Zdhhc8-knockout mouse behavioral phenotyping (prepulse inhibition, locomotor activity, MK801 response)","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout mouse with defined behavioral phenotypes and splice-regulatory mechanism, single lab","pmids":["15184899"],"is_preprint":false},{"year":2013,"finding":"DHHC8 binds and palmitoylates PICK1 at a cysteine residue essential for long-term synaptic depression (LTD) in cerebellar Purkinje neurons; induction of LTD requires DHHC8, and PICK1 palmitoylation by DHHC8 is necessary for this form of synaptic plasticity.","method":"Co-IP/binding assays, palmitoylation assays, DHHC8 loss-of-function in cultured cerebellar Purkinje neurons, site-directed mutagenesis of PICK1 cysteine, electrophysiological LTD readout","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — substrate identification with palmitoylation assay, mutagenesis, and functional LTD readout in neurons; multiple orthogonal methods in one study","pmids":["24068808"],"is_preprint":false},{"year":2019,"finding":"Drosophila ZDHHC8 ortholog (dZDHHC8/CG34449) palmitoylates scribble and Ras64B; knockdown causes tissue overgrowth and dZDHHC8 mutants are larval lethal, establishing a role in growth and viability control.","method":"Drosophila genetics (knockdown, mutant generation), palmitoylation substrate screen from publicly available data, candidate substrate identification (scribble, Ras64B)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic loss-of-function in Drosophila with growth phenotype and substrate candidates, but palmitoylation of substrates not rigorously validated biochemically in the abstract","pmids":["30735487"],"is_preprint":false},{"year":2020,"finding":"ZDHHC5 and ZDHHC8 are uniquely enriched in DRG axons among all mammalian PATs; both are required for Gp130/JAK/STAT3 axon-to-soma retrograde signaling but not DLK/JNK signaling. ZDHHC5 and ZDHHC8 palmitoylate Gp130, and their knockdown reduces Gp130 palmitoylation and surface expression in DRG neurons.","method":"Subcellular fractionation/imaging for PAT localization in DRG neurons, shRNA knockdown (Zdhhc5/8), co-transfection palmitoylation assay for Gp130 in non-neuronal cells, STAT3 signaling assay, surface expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, palmitoylation assay, signaling pathway epistasis, surface expression), single lab but rigorous design","pmids":["32958558"],"is_preprint":false},{"year":2018,"finding":"ZDHHC8 facilitates GluA1 (AMPA receptor subunit) trafficking to the neuronal surface in the hippocampus and modulates AMPA receptor-mediated excitatory synaptic neurotransmission, including inward rectification of AMPA currents; ZDHHC8 knockdown reduces and overexpression increases neuronal hyperexcitability and seizure susceptibility.","method":"rAAV-mediated knockdown/overexpression in mice, whole-cell patch-clamp recordings in hippocampal slices, immunoprecipitation and Western blot for GluA1 surface trafficking, kainate/pilocarpine seizure models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain-of-function with electrophysiological and biochemical readouts, single lab","pmids":["30038264"],"is_preprint":false},{"year":2023,"finding":"ZDHHC8 (but not ZDHHC5) palmitoylates the 190 kDa isoform of ankyrin-G (AnkG-190) at Cys70, stabilizing its localization in dendritic spine heads and at dendritic plasma membrane nanodomains; mutation of Cys70 impairs AnkG-190 function and alters PSD-95 scaffolding. Lithium inhibits ZDHHC8, reducing AnkG-190 palmitoylation and increasing its mobility in dendritic spines.","method":"Palmitoylation assays, site-directed mutagenesis (Cys70), live imaging/FRAP in dendritic spines, ZDHHC8 overexpression/knockdown, lithium treatment","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation assay with mutagenesis, live imaging with functional consequence, single lab","pmids":["36969554"],"is_preprint":false},{"year":2024,"finding":"ZDHHC8 catalyzes S-palmitoylation of SLC7A11 at Cys327 in glioblastoma cells, which decreases SLC7A11 ubiquitination and stabilizes the protein, promoting ferroptosis resistance. AMPKα1 directly phosphorylates ZDHHC8 at Ser299, strengthening the ZDHHC8–SLC7A11 interaction and enhancing SLC7A11 palmitoylation and deubiquitination; ZDHHC8 knockdown impairs GBM cell survival via ferroptosis.","method":"S-palmitoylation assays, ubiquitination assays, site-directed mutagenesis (SLC7A11 Cys327, ZDHHC8 S299), Co-IP, ZDHHC8 knockdown in GBM cells with ferroptosis readouts, ectopic SLC7A11 rescue experiments","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including palmitoylation assay, mutagenesis at substrate site, phosphorylation mapping, ubiquitination assay, and functional rescue; single lab but rigorous multi-method design","pmids":["38211651"],"is_preprint":false},{"year":2025,"finding":"ZDHHC8 palmitoylates GPX4 at Cys75, and this palmitoylation is required for GPX4 stability and ferroptosis resistance. PF-670462, identified as a ZDHHC8-specific inhibitor, promotes ZDHHC8 degradation, attenuates GPX4 palmitoylation, enhances ferroptosis sensitivity, and facilitates CD8+ T cell-induced tumor cell ferroptosis, improving cancer immunotherapy efficacy.","method":"S-palmitoylation assays, site-directed mutagenesis (GPX4 Cys75), small-molecule drug screening, ZDHHC8 knockdown/inhibition, B16-F10 xenograft mouse model, ferroptosis assays, immunotherapy efficacy readout","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — palmitoylation assay with mutagenesis, pharmacological inhibitor with mechanistic validation, in vivo xenograft model; multiple orthogonal methods","pmids":["40108413"],"is_preprint":false},{"year":2025,"finding":"ZDHHC8 knockdown enhances chemotherapy sensitivity in high-grade serous ovarian cancer cells by upregulating β-catenin-mediated chemoresistance; KLF5 transcription factor directly binds the ZDHHC8 promoter and upregulates ZDHHC8 expression, establishing a KLF5-ZDHHC8-β-catenin axis.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, ZDHHC8 knockdown/overexpression, cisplatin IC50/apoptosis assays, β-catenin inhibitor rescue, animal models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for transcriptional regulation, functional KD/OE with pathway rescue, single lab","pmids":["40681764"],"is_preprint":false},{"year":2025,"finding":"Drosophila ZDHHC8 (CG34449/Zdhhc8) palmitoylates Gαq, promoting Gαq membrane localization and function; loss of Zdhhc8 markedly reduces Gαq palmitoylation, attenuates AkhR/Gαq GPCR signaling, and reduces receptor stability. A genome-wide CRISPR screen in Drosophila identified Zdhhc8 as a top hit required for robust Gαq-mediated signaling.","method":"Genome-wide CRISPR knockout screen (Drosophila), palmitoylation assays for Gαq, membrane localization assays, genetic loss-of-function (Zdhhc8 KO), GPCR signaling readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide screen with mechanistic follow-up (palmitoylation assay, localization, signaling), preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.08.06.668953"],"is_preprint":true},{"year":2011,"finding":"ZDHHC8 knockdown in mesothelioma cells impairs the G2/M checkpoint after X-irradiation, leading to chromosomal instability (increased micronuclei), increased apoptosis, and enhanced radiosensitivity in vitro and tumor growth suppression in vivo.","method":"siRNA knockdown, cell survival assays after X-irradiation, cell cycle analysis (G2/M checkpoint), micronuclei quantification, apoptosis assays, in vivo tumor xenograft","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with defined cell cycle and apoptotic phenotype in vitro and in vivo, single lab; no direct substrate identified","pmids":["22017350"],"is_preprint":false}],"current_model":"ZDHHC8 is a transmembrane palmitoyl acyltransferase that S-palmitoylates multiple substrates including PICK1 (required for cerebellar LTD), Gp130 (regulating axonal retrograde signaling), GluA1 (controlling AMPA receptor surface trafficking and seizure susceptibility), ankyrin-G-190 (stabilizing its dendritic spine localization, inhibited by lithium), SLC7A11 (protecting against ferroptosis via reduced ubiquitination, regulated upstream by AMPKα1 phosphorylation of ZDHHC8 at S299), and GPX4 (at Cys75, conferring ferroptosis resistance in tumors); in addition, ZDHHC8 palmitoylates Gαq to sustain membrane localization and GPCR signaling, and its transcription is directly driven by KLF5, placing ZDHHC8 at the center of a KLF5-ZDHHC8-β-catenin chemoresistance axis in ovarian cancer."},"narrative":{"mechanistic_narrative":"ZDHHC8 is a transmembrane palmitoyl acyltransferase that S-palmitoylates a diverse set of substrates to control neuronal signaling, synaptic plasticity, and cancer-cell survival [PMID:24068808, PMID:38211651]. In the nervous system it palmitoylates PICK1 at a cysteine essential for cerebellar long-term depression [PMID:24068808], drives GluA1/AMPA-receptor surface trafficking and seizure susceptibility [PMID:30038264], stabilizes the dendritic-spine localization of the 190 kDa ankyrin-G isoform at Cys70 in a lithium-inhibited reaction [PMID:36969554], and—together with ZDHHC5—palmitoylates Gp130 to sustain its surface expression and JAK/STAT3 retrograde axonal signaling in DRG neurons [PMID:32958558]. Consistent with these palmitoylation-dependent neuronal roles, a splice-regulatory SNP and Zdhhc8 knockout produce psychiatric-relevant behavioral deficits in mice [PMID:15184899]. In tumors ZDHHC8 promotes ferroptosis resistance by palmitoylating SLC7A11 at Cys327 to reduce its ubiquitination and stabilize the protein—an interaction strengthened by AMPKα1 phosphorylation of ZDHHC8 at Ser299—and by palmitoylating GPX4 at Cys75 to maintain GPX4 stability, with the inhibitor PF-670462 reversing both to sensitize tumors to ferroptosis and immunotherapy [PMID:38211651, PMID:40108413]. ZDHHC8 expression is directly driven by KLF5, defining a KLF5–ZDHHC8–β-catenin axis that confers chemoresistance in ovarian cancer [PMID:40681764].","teleology":[{"year":2004,"claim":"Established ZDHHC8 as a candidate neuronal palmitoyltransferase whose expression is splice-regulated and whose loss produces psychiatric-relevant behavioral phenotypes, linking palmitoylation to brain function.","evidence":"SNP genotyping/splice analysis and Zdhhc8-knockout mouse behavioral phenotyping","pmids":["15184899"],"confidence":"Medium","gaps":["No direct neuronal substrate identified at this stage","Mechanism connecting palmitoyltransferase activity to behavior unresolved"]},{"year":2011,"claim":"Showed ZDHHC8 supports the G2/M checkpoint and genomic stability, providing the first evidence of a role in cancer-cell survival independent of any identified substrate.","evidence":"siRNA knockdown in mesothelioma with cell-cycle, micronuclei, apoptosis, and xenograft readouts","pmids":["22017350"],"confidence":"Medium","gaps":["No palmitoylation substrate linking ZDHHC8 to checkpoint control","Catalytic dependence not tested"]},{"year":2013,"claim":"Identified PICK1 as a direct ZDHHC8 substrate and connected its palmitoylation to a defined form of synaptic plasticity, moving from candidate enzyme to mechanistic substrate-function chain.","evidence":"Co-IP/palmitoylation assays, PICK1 cysteine mutagenesis, and LTD electrophysiology in cerebellar Purkinje neurons","pmids":["24068808"],"confidence":"High","gaps":["Whether other synaptic substrates contribute to plasticity not addressed","In vivo requirement not tested"]},{"year":2018,"claim":"Extended ZDHHC8's synaptic role to AMPA-receptor trafficking, linking it bidirectionally to neuronal excitability and seizure susceptibility.","evidence":"rAAV knockdown/overexpression in mice, patch-clamp, GluA1 surface biochemistry, and seizure models","pmids":["30038264"],"confidence":"Medium","gaps":["Direct palmitoylation of GluA1 versus indirect trafficking effect not fully resolved","Single lab"]},{"year":2020,"claim":"Demonstrated axonal enrichment of ZDHHC8 and its requirement, with ZDHHC5, for Gp130 palmitoylation and retrograde JAK/STAT3 signaling, defining pathway specificity.","evidence":"PAT localization in DRG neurons, shRNA knockdown, Gp130 palmitoylation assay, STAT3 signaling and surface-expression readouts","pmids":["32958558"],"confidence":"High","gaps":["Relative contribution of ZDHHC8 versus ZDHHC5 not dissected","Palmitoylation site on Gp130 not mapped"]},{"year":2023,"claim":"Mapped ankyrin-G-190 Cys70 as a ZDHHC8 site controlling dendritic-spine nanodomain stability and showed lithium acts as a ZDHHC8 inhibitor, providing a pharmacological handle.","evidence":"Palmitoylation assays, Cys70 mutagenesis, FRAP imaging, and lithium treatment in neurons","pmids":["36969554"],"confidence":"Medium","gaps":["Mechanism of lithium inhibition of ZDHHC8 unknown","Direct versus indirect lithium effect not separated"]},{"year":2024,"claim":"Defined a ferroptosis-protective axis in which ZDHHC8 palmitoylates SLC7A11 at Cys327 to block ubiquitination, with AMPKα1 phosphorylation at Ser299 tuning the interaction, integrating ZDHHC8 into metabolic-stress signaling.","evidence":"Palmitoylation and ubiquitination assays, substrate (Cys327) and enzyme (Ser299) mutagenesis, Co-IP, and ferroptosis rescue in glioblastoma cells","pmids":["38211651"],"confidence":"High","gaps":["No structural basis for phospho-regulated substrate binding","Generalizability beyond GBM not tested"]},{"year":2025,"claim":"Identified GPX4 Cys75 as a second ferroptosis-relevant ZDHHC8 substrate and validated PF-670462 as a ZDHHC8 inhibitor that sensitizes tumors to ferroptosis and immunotherapy.","evidence":"Palmitoylation assays, GPX4 Cys75 mutagenesis, small-molecule screening, and B16-F10 xenograft immunotherapy models","pmids":["40108413"],"confidence":"High","gaps":["Inhibitor selectivity against other ZDHHC enzymes not exhaustively defined","Whether SLC7A11 and GPX4 palmitoylation are co-regulated unclear"]},{"year":2025,"claim":"Placed ZDHHC8 downstream of KLF5 transcriptional control in a β-catenin chemoresistance axis, connecting its regulation to ovarian cancer drug response.","evidence":"ChIP, luciferase reporter, knockdown/overexpression with cisplatin sensitivity and β-catenin rescue, animal models","pmids":["40681764"],"confidence":"Medium","gaps":["Palmitoylation substrate linking ZDHHC8 to β-catenin not identified","Catalytic requirement for chemoresistance untested"]},{"year":2025,"claim":"Established Gαq as a conserved ZDHHC8 substrate required for GPCR membrane localization and signaling using unbiased genetic screening in Drosophila.","evidence":"Genome-wide CRISPR screen and Gαq palmitoylation/localization/signaling assays in Drosophila (preprint)","pmids":["bio_10.1101_2025.08.06.668953"],"confidence":"Medium","gaps":["Not peer-reviewed","Conservation of human ZDHHC8-Gαq interaction not demonstrated"]},{"year":null,"claim":"How ZDHHC8 selects among its diverse substrates across neuronal and tumor contexts, and whether a single catalytic mechanism is differentially regulated by phosphorylation, transcription, and pharmacology, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Tissue-specific substrate prioritization mechanism unknown","Whether neuronal and oncogenic functions share regulatory inputs untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,5,6,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9]}],"complexes":[],"partners":["PICK1","GP130","GRIA1","ANK3","SLC7A11","GPX4","ZDHHC5","KLF5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULC8","full_name":"Palmitoyltransferase ZDHHC8","aliases":["Zinc finger DHHC domain-containing protein 8","DHHC-8","Zinc finger protein 378"],"length_aa":765,"mass_kda":81.4,"function":"Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates and therefore functions in several unrelated biological processes (Probable). Through the palmitoylation of ABCA1 regulates the localization of the transporter to the plasma membrane and thereby regulates its function in cholesterol and phospholipid efflux (Probable). Could also pamitoylate the D(2) dopamine receptor DRD2 and regulate its stability and localization to the plasma membrane (Probable). Could also play a role in glutamatergic transmission (By similarity) (Microbial infection) Able to palmitoylate SARS coronavirus-2/SARS-CoV-2 spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell","subcellular_location":"Golgi apparatus membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULC8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZDHHC8","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZDHHC8","total_profiled":1310},"omim":[{"mim_id":"621547","title":"ZDHHC PALMITOYLTRANSFERASE 4; ZDHHC4","url":"https://www.omim.org/entry/621547"},{"mim_id":"617150","title":"ZDHHC PALMITOYLTRANSFERASE 3; ZDHHC3","url":"https://www.omim.org/entry/617150"},{"mim_id":"608784","title":"ZDHHC PALMITOYLTRANSFERASE 8; ZDHHC8","url":"https://www.omim.org/entry/608784"},{"mim_id":"181500","title":"SCHIZOPHRENIA; SCZD","url":"https://www.omim.org/entry/181500"},{"mim_id":"126450","title":"DOPAMINE RECEPTOR D2; DRD2","url":"https://www.omim.org/entry/126450"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZDHHC8"},"hgnc":{"alias_symbol":["ZNF378","KIAA1292","DHHC8"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULC8","domains":[{"cath_id":"-","chopping":"75-134","consensus_level":"medium","plddt":82.7877,"start":75,"end":134},{"cath_id":"1.20.1440","chopping":"26-69_145-224","consensus_level":"medium","plddt":96.5141,"start":26,"end":224}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULC8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULC8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULC8-F1-predicted_aligned_error_v6.png","plddt_mean":56.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZDHHC8","jax_strain_url":"https://www.jax.org/strain/search?query=ZDHHC8"},"sequence":{"accession":"Q9ULC8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULC8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULC8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULC8"}},"corpus_meta":[{"pmid":"15184899","id":"PMC_15184899","title":"Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15184899","citation_count":260,"is_preprint":false},{"pmid":"40108413","id":"PMC_40108413","title":"Palmitoylation of GPX4 via the targetable ZDHHC8 determines ferroptosis sensitivity and antitumor immunity.","date":"2025","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40108413","citation_count":78,"is_preprint":false},{"pmid":"15489219","id":"PMC_15489219","title":"Case-control study and transmission disequilibrium test provide consistent evidence for association between schizophrenia and genetic variation in the 22q11 gene ZDHHC8.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15489219","citation_count":77,"is_preprint":false},{"pmid":"38211651","id":"PMC_38211651","title":"AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38211651","citation_count":64,"is_preprint":false},{"pmid":"24068808","id":"PMC_24068808","title":"DHHC8-dependent PICK1 palmitoylation is required for induction of cerebellar long-term synaptic depression.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24068808","citation_count":57,"is_preprint":false},{"pmid":"15992527","id":"PMC_15992527","title":"No association between the putative functional ZDHHC8 single nucleotide polymorphism rs175174 and schizophrenia in large European samples.","date":"2005","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/15992527","citation_count":36,"is_preprint":false},{"pmid":"16860541","id":"PMC_16860541","title":"Analysis of ProDH, COMT and ZDHHC8 risk variants does not support individual or interactive effects on schizophrenia susceptibility.","date":"2006","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/16860541","citation_count":34,"is_preprint":false},{"pmid":"20661937","id":"PMC_20661937","title":"Testing for genetic association between the ZDHHC8 gene locus and susceptibility to schizophrenia: An integrated analysis of multiple datasets.","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20661937","citation_count":33,"is_preprint":false},{"pmid":"16150541","id":"PMC_16150541","title":"The ZDHHC8 gene did not associate with bipolar disorder or schizophrenia.","date":"2005","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/16150541","citation_count":32,"is_preprint":false},{"pmid":"32958558","id":"PMC_32958558","title":"The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32958558","citation_count":32,"is_preprint":false},{"pmid":"22017350","id":"PMC_22017350","title":"ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model.","date":"2011","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/22017350","citation_count":31,"is_preprint":false},{"pmid":"16225675","id":"PMC_16225675","title":"ZDHHC8 as a candidate gene for schizophrenia: analysis of a putative functional intronic marker in case-control and family-based association studies.","date":"2005","source":"BMC psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16225675","citation_count":27,"is_preprint":false},{"pmid":"30038264","id":"PMC_30038264","title":"ZDHHC8 critically regulates seizure susceptibility in epilepsy.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30038264","citation_count":25,"is_preprint":false},{"pmid":"20468065","id":"PMC_20468065","title":"Association of ZDHHC8 polymorphisms with smooth pursuit eye movement abnormality.","date":"2010","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20468065","citation_count":21,"is_preprint":false},{"pmid":"23403413","id":"PMC_23403413","title":"ZDHHC8 gene may play a role in cortical volumes of patients with schizophrenia.","date":"2013","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/23403413","citation_count":20,"is_preprint":false},{"pmid":"30735487","id":"PMC_30735487","title":"Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30735487","citation_count":13,"is_preprint":false},{"pmid":"36969554","id":"PMC_36969554","title":"Palmitoylation controls the stability of 190 kDa ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36969554","citation_count":5,"is_preprint":false},{"pmid":"40759219","id":"PMC_40759219","title":"zDHHC8 suppresses infection-induced necroptosis in monocyte/macrophages through palmitoylation of necrosome components in large yellow croaker (Larimichthys crocea).","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40759219","citation_count":3,"is_preprint":false},{"pmid":"40681764","id":"PMC_40681764","title":"KLF5-regulated ZDHHC8 reduces chemosensitivity in high-grade serous ovarian cancer through β-catenin signaling.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40681764","citation_count":0,"is_preprint":false},{"pmid":"41740333","id":"PMC_41740333","title":"Yitangkang decoction in the treatment of glomerular filtration barrier damage through AMPKα1/ZDHHC8/SLC7A11/GPX4 and TGF-β/Smad signaling pathways: A multi-omics analysis.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41740333","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.06.668953","title":"A Genome-wide CRISPR Screen Reveals ZDHHC8-Dependent G  <sub>α</sub>  q Palmitoylation as a Key Regulator of GPCR Signaling","date":"2025-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.06.668953","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12913,"output_tokens":3375,"usd":0.044682,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10853,"output_tokens":3576,"usd":0.071832,"stage2_stop_reason":"end_turn"},"total_usd":0.116514,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"ZDHHC8 encodes a putative transmembrane palmitoyltransferase; a SNP (rs175174) in intron 4 modulates retention of intron 4, regulating the level of the fully functional transcript. Zdhhc8-knockout mice show sexually dimorphic prepulse inhibition deficits and decreased sensitivity to MK801, implicating ZDHHC8-dependent palmitoylation of neuronal proteins in psychiatric phenotypes.\",\n      \"method\": \"SNP genotyping, splice analysis, Zdhhc8-knockout mouse behavioral phenotyping (prepulse inhibition, locomotor activity, MK801 response)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout mouse with defined behavioral phenotypes and splice-regulatory mechanism, single lab\",\n      \"pmids\": [\"15184899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DHHC8 binds and palmitoylates PICK1 at a cysteine residue essential for long-term synaptic depression (LTD) in cerebellar Purkinje neurons; induction of LTD requires DHHC8, and PICK1 palmitoylation by DHHC8 is necessary for this form of synaptic plasticity.\",\n      \"method\": \"Co-IP/binding assays, palmitoylation assays, DHHC8 loss-of-function in cultured cerebellar Purkinje neurons, site-directed mutagenesis of PICK1 cysteine, electrophysiological LTD readout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — substrate identification with palmitoylation assay, mutagenesis, and functional LTD readout in neurons; multiple orthogonal methods in one study\",\n      \"pmids\": [\"24068808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Drosophila ZDHHC8 ortholog (dZDHHC8/CG34449) palmitoylates scribble and Ras64B; knockdown causes tissue overgrowth and dZDHHC8 mutants are larval lethal, establishing a role in growth and viability control.\",\n      \"method\": \"Drosophila genetics (knockdown, mutant generation), palmitoylation substrate screen from publicly available data, candidate substrate identification (scribble, Ras64B)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic loss-of-function in Drosophila with growth phenotype and substrate candidates, but palmitoylation of substrates not rigorously validated biochemically in the abstract\",\n      \"pmids\": [\"30735487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZDHHC5 and ZDHHC8 are uniquely enriched in DRG axons among all mammalian PATs; both are required for Gp130/JAK/STAT3 axon-to-soma retrograde signaling but not DLK/JNK signaling. ZDHHC5 and ZDHHC8 palmitoylate Gp130, and their knockdown reduces Gp130 palmitoylation and surface expression in DRG neurons.\",\n      \"method\": \"Subcellular fractionation/imaging for PAT localization in DRG neurons, shRNA knockdown (Zdhhc5/8), co-transfection palmitoylation assay for Gp130 in non-neuronal cells, STAT3 signaling assay, surface expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, palmitoylation assay, signaling pathway epistasis, surface expression), single lab but rigorous design\",\n      \"pmids\": [\"32958558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZDHHC8 facilitates GluA1 (AMPA receptor subunit) trafficking to the neuronal surface in the hippocampus and modulates AMPA receptor-mediated excitatory synaptic neurotransmission, including inward rectification of AMPA currents; ZDHHC8 knockdown reduces and overexpression increases neuronal hyperexcitability and seizure susceptibility.\",\n      \"method\": \"rAAV-mediated knockdown/overexpression in mice, whole-cell patch-clamp recordings in hippocampal slices, immunoprecipitation and Western blot for GluA1 surface trafficking, kainate/pilocarpine seizure models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain-of-function with electrophysiological and biochemical readouts, single lab\",\n      \"pmids\": [\"30038264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC8 (but not ZDHHC5) palmitoylates the 190 kDa isoform of ankyrin-G (AnkG-190) at Cys70, stabilizing its localization in dendritic spine heads and at dendritic plasma membrane nanodomains; mutation of Cys70 impairs AnkG-190 function and alters PSD-95 scaffolding. Lithium inhibits ZDHHC8, reducing AnkG-190 palmitoylation and increasing its mobility in dendritic spines.\",\n      \"method\": \"Palmitoylation assays, site-directed mutagenesis (Cys70), live imaging/FRAP in dendritic spines, ZDHHC8 overexpression/knockdown, lithium treatment\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation assay with mutagenesis, live imaging with functional consequence, single lab\",\n      \"pmids\": [\"36969554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZDHHC8 catalyzes S-palmitoylation of SLC7A11 at Cys327 in glioblastoma cells, which decreases SLC7A11 ubiquitination and stabilizes the protein, promoting ferroptosis resistance. AMPKα1 directly phosphorylates ZDHHC8 at Ser299, strengthening the ZDHHC8–SLC7A11 interaction and enhancing SLC7A11 palmitoylation and deubiquitination; ZDHHC8 knockdown impairs GBM cell survival via ferroptosis.\",\n      \"method\": \"S-palmitoylation assays, ubiquitination assays, site-directed mutagenesis (SLC7A11 Cys327, ZDHHC8 S299), Co-IP, ZDHHC8 knockdown in GBM cells with ferroptosis readouts, ectopic SLC7A11 rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including palmitoylation assay, mutagenesis at substrate site, phosphorylation mapping, ubiquitination assay, and functional rescue; single lab but rigorous multi-method design\",\n      \"pmids\": [\"38211651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC8 palmitoylates GPX4 at Cys75, and this palmitoylation is required for GPX4 stability and ferroptosis resistance. PF-670462, identified as a ZDHHC8-specific inhibitor, promotes ZDHHC8 degradation, attenuates GPX4 palmitoylation, enhances ferroptosis sensitivity, and facilitates CD8+ T cell-induced tumor cell ferroptosis, improving cancer immunotherapy efficacy.\",\n      \"method\": \"S-palmitoylation assays, site-directed mutagenesis (GPX4 Cys75), small-molecule drug screening, ZDHHC8 knockdown/inhibition, B16-F10 xenograft mouse model, ferroptosis assays, immunotherapy efficacy readout\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — palmitoylation assay with mutagenesis, pharmacological inhibitor with mechanistic validation, in vivo xenograft model; multiple orthogonal methods\",\n      \"pmids\": [\"40108413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZDHHC8 knockdown enhances chemotherapy sensitivity in high-grade serous ovarian cancer cells by upregulating β-catenin-mediated chemoresistance; KLF5 transcription factor directly binds the ZDHHC8 promoter and upregulates ZDHHC8 expression, establishing a KLF5-ZDHHC8-β-catenin axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, ZDHHC8 knockdown/overexpression, cisplatin IC50/apoptosis assays, β-catenin inhibitor rescue, animal models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for transcriptional regulation, functional KD/OE with pathway rescue, single lab\",\n      \"pmids\": [\"40681764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drosophila ZDHHC8 (CG34449/Zdhhc8) palmitoylates Gαq, promoting Gαq membrane localization and function; loss of Zdhhc8 markedly reduces Gαq palmitoylation, attenuates AkhR/Gαq GPCR signaling, and reduces receptor stability. A genome-wide CRISPR screen in Drosophila identified Zdhhc8 as a top hit required for robust Gαq-mediated signaling.\",\n      \"method\": \"Genome-wide CRISPR knockout screen (Drosophila), palmitoylation assays for Gαq, membrane localization assays, genetic loss-of-function (Zdhhc8 KO), GPCR signaling readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide screen with mechanistic follow-up (palmitoylation assay, localization, signaling), preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.06.668953\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZDHHC8 knockdown in mesothelioma cells impairs the G2/M checkpoint after X-irradiation, leading to chromosomal instability (increased micronuclei), increased apoptosis, and enhanced radiosensitivity in vitro and tumor growth suppression in vivo.\",\n      \"method\": \"siRNA knockdown, cell survival assays after X-irradiation, cell cycle analysis (G2/M checkpoint), micronuclei quantification, apoptosis assays, in vivo tumor xenograft\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD with defined cell cycle and apoptotic phenotype in vitro and in vivo, single lab; no direct substrate identified\",\n      \"pmids\": [\"22017350\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZDHHC8 is a transmembrane palmitoyl acyltransferase that S-palmitoylates multiple substrates including PICK1 (required for cerebellar LTD), Gp130 (regulating axonal retrograde signaling), GluA1 (controlling AMPA receptor surface trafficking and seizure susceptibility), ankyrin-G-190 (stabilizing its dendritic spine localization, inhibited by lithium), SLC7A11 (protecting against ferroptosis via reduced ubiquitination, regulated upstream by AMPKα1 phosphorylation of ZDHHC8 at S299), and GPX4 (at Cys75, conferring ferroptosis resistance in tumors); in addition, ZDHHC8 palmitoylates Gαq to sustain membrane localization and GPCR signaling, and its transcription is directly driven by KLF5, placing ZDHHC8 at the center of a KLF5-ZDHHC8-β-catenin chemoresistance axis in ovarian cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZDHHC8 is a transmembrane palmitoyl acyltransferase that S-palmitoylates a diverse set of substrates to control neuronal signaling, synaptic plasticity, and cancer-cell survival [#1, #6]. In the nervous system it palmitoylates PICK1 at a cysteine essential for cerebellar long-term depression [#1], drives GluA1/AMPA-receptor surface trafficking and seizure susceptibility [#4], stabilizes the dendritic-spine localization of the 190 kDa ankyrin-G isoform at Cys70 in a lithium-inhibited reaction [#5], and—together with ZDHHC5—palmitoylates Gp130 to sustain its surface expression and JAK/STAT3 retrograde axonal signaling in DRG neurons [#3]. Consistent with these palmitoylation-dependent neuronal roles, a splice-regulatory SNP and Zdhhc8 knockout produce psychiatric-relevant behavioral deficits in mice [#0]. In tumors ZDHHC8 promotes ferroptosis resistance by palmitoylating SLC7A11 at Cys327 to reduce its ubiquitination and stabilize the protein—an interaction strengthened by AMPKα1 phosphorylation of ZDHHC8 at Ser299—and by palmitoylating GPX4 at Cys75 to maintain GPX4 stability, with the inhibitor PF-670462 reversing both to sensitize tumors to ferroptosis and immunotherapy [#6, #7]. ZDHHC8 expression is directly driven by KLF5, defining a KLF5–ZDHHC8–β-catenin axis that confers chemoresistance in ovarian cancer [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established ZDHHC8 as a candidate neuronal palmitoyltransferase whose expression is splice-regulated and whose loss produces psychiatric-relevant behavioral phenotypes, linking palmitoylation to brain function.\",\n      \"evidence\": \"SNP genotyping/splice analysis and Zdhhc8-knockout mouse behavioral phenotyping\",\n      \"pmids\": [\"15184899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct neuronal substrate identified at this stage\", \"Mechanism connecting palmitoyltransferase activity to behavior unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed ZDHHC8 supports the G2/M checkpoint and genomic stability, providing the first evidence of a role in cancer-cell survival independent of any identified substrate.\",\n      \"evidence\": \"siRNA knockdown in mesothelioma with cell-cycle, micronuclei, apoptosis, and xenograft readouts\",\n      \"pmids\": [\"22017350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No palmitoylation substrate linking ZDHHC8 to checkpoint control\", \"Catalytic dependence not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified PICK1 as a direct ZDHHC8 substrate and connected its palmitoylation to a defined form of synaptic plasticity, moving from candidate enzyme to mechanistic substrate-function chain.\",\n      \"evidence\": \"Co-IP/palmitoylation assays, PICK1 cysteine mutagenesis, and LTD electrophysiology in cerebellar Purkinje neurons\",\n      \"pmids\": [\"24068808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other synaptic substrates contribute to plasticity not addressed\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended ZDHHC8's synaptic role to AMPA-receptor trafficking, linking it bidirectionally to neuronal excitability and seizure susceptibility.\",\n      \"evidence\": \"rAAV knockdown/overexpression in mice, patch-clamp, GluA1 surface biochemistry, and seizure models\",\n      \"pmids\": [\"30038264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct palmitoylation of GluA1 versus indirect trafficking effect not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated axonal enrichment of ZDHHC8 and its requirement, with ZDHHC5, for Gp130 palmitoylation and retrograde JAK/STAT3 signaling, defining pathway specificity.\",\n      \"evidence\": \"PAT localization in DRG neurons, shRNA knockdown, Gp130 palmitoylation assay, STAT3 signaling and surface-expression readouts\",\n      \"pmids\": [\"32958558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ZDHHC8 versus ZDHHC5 not dissected\", \"Palmitoylation site on Gp130 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped ankyrin-G-190 Cys70 as a ZDHHC8 site controlling dendritic-spine nanodomain stability and showed lithium acts as a ZDHHC8 inhibitor, providing a pharmacological handle.\",\n      \"evidence\": \"Palmitoylation assays, Cys70 mutagenesis, FRAP imaging, and lithium treatment in neurons\",\n      \"pmids\": [\"36969554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of lithium inhibition of ZDHHC8 unknown\", \"Direct versus indirect lithium effect not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a ferroptosis-protective axis in which ZDHHC8 palmitoylates SLC7A11 at Cys327 to block ubiquitination, with AMPKα1 phosphorylation at Ser299 tuning the interaction, integrating ZDHHC8 into metabolic-stress signaling.\",\n      \"evidence\": \"Palmitoylation and ubiquitination assays, substrate (Cys327) and enzyme (Ser299) mutagenesis, Co-IP, and ferroptosis rescue in glioblastoma cells\",\n      \"pmids\": [\"38211651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for phospho-regulated substrate binding\", \"Generalizability beyond GBM not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified GPX4 Cys75 as a second ferroptosis-relevant ZDHHC8 substrate and validated PF-670462 as a ZDHHC8 inhibitor that sensitizes tumors to ferroptosis and immunotherapy.\",\n      \"evidence\": \"Palmitoylation assays, GPX4 Cys75 mutagenesis, small-molecule screening, and B16-F10 xenograft immunotherapy models\",\n      \"pmids\": [\"40108413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor selectivity against other ZDHHC enzymes not exhaustively defined\", \"Whether SLC7A11 and GPX4 palmitoylation are co-regulated unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ZDHHC8 downstream of KLF5 transcriptional control in a β-catenin chemoresistance axis, connecting its regulation to ovarian cancer drug response.\",\n      \"evidence\": \"ChIP, luciferase reporter, knockdown/overexpression with cisplatin sensitivity and β-catenin rescue, animal models\",\n      \"pmids\": [\"40681764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Palmitoylation substrate linking ZDHHC8 to β-catenin not identified\", \"Catalytic requirement for chemoresistance untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established Gαq as a conserved ZDHHC8 substrate required for GPCR membrane localization and signaling using unbiased genetic screening in Drosophila.\",\n      \"evidence\": \"Genome-wide CRISPR screen and Gαq palmitoylation/localization/signaling assays in Drosophila (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.06.668953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not peer-reviewed\", \"Conservation of human ZDHHC8-Gαq interaction not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZDHHC8 selects among its diverse substrates across neuronal and tumor contexts, and whether a single catalytic mechanism is differentially regulated by phosphorylation, transcription, and pharmacology, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Tissue-specific substrate prioritization mechanism unknown\", \"Whether neuronal and oncogenic functions share regulatory inputs untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 5, 6, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PICK1\", \"GP130\", \"GRIA1\", \"ANK3\", \"SLC7A11\", \"GPX4\", \"ZDHHC5\", \"KLF5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}