{"gene":"THEM6","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2022,"finding":"THEM6 is an ER membrane-associated protein that regulates intracellular levels of ether lipids and is essential for triggering the induction of the ER stress response (unfolded protein response, UPR). THEM6 loss reduces de novo sterol biosynthesis and prevents lipid-mediated activation of ATF4 in castration-resistant prostate cancer cells.","method":"THEM6 deletion in orthograft CRPC models (in vivo), combined with biochemical analysis of ether lipid levels, ER stress markers, sterol biosynthesis assays, and ATF4 activation readouts","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined cellular and molecular phenotypes, multiple orthogonal biochemical readouts (lipid levels, UPR markers, sterol biosynthesis, ATF4 activation) in a single rigorous study","pmids":["35014179"],"is_preprint":false},{"year":2025,"finding":"THEM6 stabilizes FDFT1 protein by inhibiting its K48-linked ubiquitination, thereby prolonging FDFT1 protein half-life, promoting ferroptosis, and enhancing carboplatin sensitivity in triple-negative breast cancer. THEM6 overexpression reduces GPX4 and SLC7A11 while increasing ACSL4, and FDFT1 knockdown reverses THEM6-induced carboplatin sensitivity.","method":"THEM6 overexpression in vitro and orthotopic xenograft models; ferroptosis inhibitor rescue experiments (Fer-1); Western blotting; ubiquitination assays (K48-linkage specificity); protein half-life assays; FDFT1 knockdown epistasis; ROS/iron/MDA measurements; TEM of mitochondria","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination assay, half-life, epistasis knockdown, in vivo) in a single lab study; not independently replicated","pmids":["40619388"],"is_preprint":false}],"current_model":"THEM6 is an ER membrane-associated protein that regulates ether lipid homeostasis and is required for UPR/ER stress induction, de novo sterol biosynthesis, and lipid-mediated ATF4 activation; it also stabilizes the cholesterol biosynthesis enzyme FDFT1 by inhibiting K48-linked ubiquitination, thereby promoting ferroptosis and modulating chemotherapy sensitivity."},"narrative":{"mechanistic_narrative":"THEM6 is an endoplasmic reticulum membrane-associated protein that links lipid homeostasis to stress signaling and cancer cell fate [PMID:35014179]. It regulates intracellular ether lipid levels and is required for induction of the unfolded protein response, with its loss reducing de novo sterol biosynthesis and abrogating lipid-mediated activation of the transcription factor ATF4 in castration-resistant prostate cancer cells [PMID:35014179]. THEM6 also stabilizes the cholesterol biosynthesis enzyme FDFT1 by inhibiting its K48-linked ubiquitination, thereby extending FDFT1 protein half-life; this axis shifts cells toward a ferroptosis-prone state—lowering GPX4 and SLC7A11 while raising ACSL4—and enhances carboplatin sensitivity in triple-negative breast cancer, with FDFT1 knockdown reversing the THEM6-driven sensitization [PMID:40619388]. Beyond these two studies, the catalytic activity and structural basis of THEM6 function have not been characterized in the available corpus.","teleology":[{"year":2022,"claim":"Established THEM6 as an ER membrane-associated regulator coupling ether lipid and sterol metabolism to ER stress signaling, defining its role in cancer cell adaptation.","evidence":"THEM6 deletion in orthograft castration-resistant prostate cancer models with biochemical readouts of ether lipids, UPR markers, sterol biosynthesis, and ATF4 activation","pmids":["35014179"],"confidence":"High","gaps":["The molecular/catalytic activity by which THEM6 controls ether lipid levels is not defined","The mechanism linking THEM6 to ATF4 activation and sterol biosynthesis is not resolved","No structural model or direct substrate identified"]},{"year":2025,"claim":"Identified a post-translational mechanism in which THEM6 stabilizes FDFT1 to promote ferroptosis and chemosensitivity, connecting THEM6 lipid metabolism to redox-driven cell death.","evidence":"THEM6 overexpression in vitro and orthotopic xenografts, K48-linkage ubiquitination assays, protein half-life assays, FDFT1 knockdown epistasis, and ferroptosis marker/ROS/iron measurements in triple-negative breast cancer","pmids":["40619388"],"confidence":"Medium","gaps":["Single-lab study not independently replicated","The mechanism by which THEM6 inhibits K48-linked ubiquitination of FDFT1 (direct binding vs. recruitment of a deubiquitinase) is not established","Whether THEM6 directly interacts with FDFT1 was not shown by reciprocal validation"]},{"year":null,"claim":"The biochemical activity of THEM6 itself remains undefined—whether it is an enzyme acting on lipids or an adaptor regulating other enzymes.","evidence":"No discovery in the corpus assigns a direct catalytic function or structure to THEM6","pmids":[],"confidence":"Low","gaps":["No defined enzymatic activity or substrate for THEM6","No structural characterization","Direct physical interaction partners not validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1]}],"complexes":[],"partners":["FDFT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUY1","full_name":"Protein THEM6","aliases":["Mesenchymal stem cell protein DSCD75","Thioesterase superfamily member 6"],"length_aa":208,"mass_kda":23.9,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8WUY1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/THEM6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/THEM6","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/THEM6"},"hgnc":{"alias_symbol":["DSCD75"],"prev_symbol":["C8orf55"]},"alphafold":{"accession":"Q8WUY1","domains":[{"cath_id":"3.10.129.10","chopping":"20-179","consensus_level":"medium","plddt":96.9409,"start":20,"end":179}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUY1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUY1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUY1-F1-predicted_aligned_error_v6.png","plddt_mean":94.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THEM6","jax_strain_url":"https://www.jax.org/strain/search?query=THEM6"},"sequence":{"accession":"Q8WUY1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUY1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUY1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUY1"}},"corpus_meta":[{"pmid":"24687888","id":"PMC_24687888","title":"Discovery of colorectal cancer biomarker candidates by membrane proteomic analysis and subsequent verification using selected reaction monitoring (SRM) and tissue microarray (TMA) analysis.","date":"2014","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/24687888","citation_count":63,"is_preprint":false},{"pmid":"35014179","id":"PMC_35014179","title":"THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.","date":"2022","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35014179","citation_count":24,"is_preprint":false},{"pmid":"36470533","id":"PMC_36470533","title":"The First Pituitary Proteome Landscape From Matched Anterior and Posterior Lobes for a Better Understanding of the Pituitary Gland.","date":"2022","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/36470533","citation_count":7,"is_preprint":false},{"pmid":"40619388","id":"PMC_40619388","title":"THEM6 modulates carboplatin sensitivity by regulating ferroptosis through FDFT1 in triple-negative breast cancer.","date":"2025","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/40619388","citation_count":4,"is_preprint":false},{"pmid":"35107853","id":"PMC_35107853","title":"Can THEM6 targeting stop resistance to prostate cancer treatment?","date":"2022","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35107853","citation_count":1,"is_preprint":false},{"pmid":"42092548","id":"PMC_42092548","title":"Genomic background of lactation curve parameters derived from daily milk yield in Holstein cattle using parametric functions.","date":"2026","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/42092548","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5619,"output_tokens":713,"usd":0.013776,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7127,"output_tokens":1479,"usd":0.036305,"stage2_stop_reason":"end_turn"},"total_usd":0.050081,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"THEM6 is an ER membrane-associated protein that regulates intracellular levels of ether lipids and is essential for triggering the induction of the ER stress response (unfolded protein response, UPR). THEM6 loss reduces de novo sterol biosynthesis and prevents lipid-mediated activation of ATF4 in castration-resistant prostate cancer cells.\",\n      \"method\": \"THEM6 deletion in orthograft CRPC models (in vivo), combined with biochemical analysis of ether lipid levels, ER stress markers, sterol biosynthesis assays, and ATF4 activation readouts\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined cellular and molecular phenotypes, multiple orthogonal biochemical readouts (lipid levels, UPR markers, sterol biosynthesis, ATF4 activation) in a single rigorous study\",\n      \"pmids\": [\"35014179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THEM6 stabilizes FDFT1 protein by inhibiting its K48-linked ubiquitination, thereby prolonging FDFT1 protein half-life, promoting ferroptosis, and enhancing carboplatin sensitivity in triple-negative breast cancer. THEM6 overexpression reduces GPX4 and SLC7A11 while increasing ACSL4, and FDFT1 knockdown reverses THEM6-induced carboplatin sensitivity.\",\n      \"method\": \"THEM6 overexpression in vitro and orthotopic xenograft models; ferroptosis inhibitor rescue experiments (Fer-1); Western blotting; ubiquitination assays (K48-linkage specificity); protein half-life assays; FDFT1 knockdown epistasis; ROS/iron/MDA measurements; TEM of mitochondria\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ubiquitination assay, half-life, epistasis knockdown, in vivo) in a single lab study; not independently replicated\",\n      \"pmids\": [\"40619388\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THEM6 is an ER membrane-associated protein that regulates ether lipid homeostasis and is required for UPR/ER stress induction, de novo sterol biosynthesis, and lipid-mediated ATF4 activation; it also stabilizes the cholesterol biosynthesis enzyme FDFT1 by inhibiting K48-linked ubiquitination, thereby promoting ferroptosis and modulating chemotherapy sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THEM6 is an endoplasmic reticulum membrane-associated protein that links lipid homeostasis to stress signaling and cancer cell fate [#0]. It regulates intracellular ether lipid levels and is required for induction of the unfolded protein response, with its loss reducing de novo sterol biosynthesis and abrogating lipid-mediated activation of the transcription factor ATF4 in castration-resistant prostate cancer cells [#0]. THEM6 also stabilizes the cholesterol biosynthesis enzyme FDFT1 by inhibiting its K48-linked ubiquitination, thereby extending FDFT1 protein half-life; this axis shifts cells toward a ferroptosis-prone state—lowering GPX4 and SLC7A11 while raising ACSL4—and enhances carboplatin sensitivity in triple-negative breast cancer, with FDFT1 knockdown reversing the THEM6-driven sensitization [#1]. Beyond these two studies, the catalytic activity and structural basis of THEM6 function have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Established THEM6 as an ER membrane-associated regulator coupling ether lipid and sterol metabolism to ER stress signaling, defining its role in cancer cell adaptation.\",\n      \"evidence\": \"THEM6 deletion in orthograft castration-resistant prostate cancer models with biochemical readouts of ether lipids, UPR markers, sterol biosynthesis, and ATF4 activation\",\n      \"pmids\": [\"35014179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular/catalytic activity by which THEM6 controls ether lipid levels is not defined\",\n        \"The mechanism linking THEM6 to ATF4 activation and sterol biosynthesis is not resolved\",\n        \"No structural model or direct substrate identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a post-translational mechanism in which THEM6 stabilizes FDFT1 to promote ferroptosis and chemosensitivity, connecting THEM6 lipid metabolism to redox-driven cell death.\",\n      \"evidence\": \"THEM6 overexpression in vitro and orthotopic xenografts, K48-linkage ubiquitination assays, protein half-life assays, FDFT1 knockdown epistasis, and ferroptosis marker/ROS/iron measurements in triple-negative breast cancer\",\n      \"pmids\": [\"40619388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study not independently replicated\",\n        \"The mechanism by which THEM6 inhibits K48-linked ubiquitination of FDFT1 (direct binding vs. recruitment of a deubiquitinase) is not established\",\n        \"Whether THEM6 directly interacts with FDFT1 was not shown by reciprocal validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of THEM6 itself remains undefined—whether it is an enzyme acting on lipids or an adaptor regulating other enzymes.\",\n      \"evidence\": \"No discovery in the corpus assigns a direct catalytic function or structure to THEM6\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No defined enzymatic activity or substrate for THEM6\",\n        \"No structural characterization\",\n        \"Direct physical interaction partners not validated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FDFT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}