{"gene":"CD36","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1989,"finding":"CD36 (GPIV) directly binds collagen Type I fibrils with high affinity (Kd ~0.34 nM) and mediates the early stages of platelet adhesion and activation in response to collagen, as demonstrated by competitive inhibition with purified GPIV and Fab fragments of anti-GPIV antibody blocking collagen-induced shape change, aggregation, and secretion.","method":"Direct binding assay of purified GPIV to collagen fibrils; competitive inhibition with purified GPIV and Fab fragments of polyclonal anti-GPIV antibody; platelet adhesion/aggregation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay with Kd measurement, competitive inhibition, multiple orthogonal functional assays in a single rigorous study","pmids":["2468670"],"is_preprint":false},{"year":1989,"finding":"CD36 (GPIV) is a heavily O- and N-glycosylated integral membrane glycoprotein (~88 kDa, 26% carbohydrate) with an N-terminal hydrophilic domain followed by a transmembrane domain, as determined by amino acid sequencing (first 36 residues via Edman degradation), carbohydrate composition analysis, and surface localization confirmed by flow cytometry and immunoprecipitation.","method":"Protein purification, Edman degradation N-terminal sequencing, carbohydrate composition analysis, flow cytometry, immunoprecipitation, radiolabeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical characterization with multiple orthogonal methods in a single dedicated study","pmids":["2468669"],"is_preprint":false},{"year":1992,"finding":"CD36-thrombospondin-1 (TSP-1) interaction occurs via a two-step mechanism: the CD36 sequence 139–155 binds first to TSP-1, inducing a conformational change that exposes a second high-affinity site on TSP-1 that then engages CD36 sequence 93–110. Peptide 139–155 augments rather than inhibits CD36-TSP binding, while peptide 93–110 blocks it.","method":"Synthetic CD36 peptide competition assays; solid-phase TSP binding; OKM5 epitope mapping; platelet aggregation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted binding with multiple peptides and orthogonal assays establishing a two-step mechanism in a single rigorous study","pmids":["1381367"],"is_preprint":false},{"year":2003,"finding":"CD36 is the endothelial cell receptor for thrombospondin-1 (TSP-1) and mediates its anti-angiogenic activity. Binding is mediated by the TSP type I repeat (TSR-1) domain of TSP-1 interacting with a conserved domain called CLESH-1 in CD36. Histidine-rich glycoprotein (HRGP) acts as a soluble decoy blocking TSP-1 binding to CD36, thereby inhibiting the anti-angiogenic response.","method":"Structure-function analysis of TSP-1 and CD36 domains; competition binding experiments; in vivo angiogenesis models","journal":"Frontiers in bioscience : a journal and virtual library","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function data and in vivo models but review article summarizing prior experiments; CLESH-1/TSR-1 interaction established in cited primary work","pmids":["12957861"],"is_preprint":false},{"year":2004,"finding":"CD36/FAT regulates fatty acid transport into cardiac and skeletal muscle cells; null mutation reduces FA uptake and metabolism while overexpression increases it. CD36 is also localized on the mitochondrial membrane and participates in FA transport across the mitochondrial membrane. Insulin and muscle contraction acutely translocate CD36 from an intracellular depot to the plasma membrane within minutes to increase FA transport.","method":"Genetic null mutation and overexpression studies; subcellular fractionation showing mitochondrial localization; radiolabeled FA uptake assays; insulin/contraction stimulation experiments in muscle","journal":"The Proceedings of the Nutrition Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/OE with defined FA uptake phenotype and subcellular localization by fractionation; single review summarizing replicated findings from multiple labs","pmids":["15294038"],"is_preprint":false},{"year":2009,"finding":"CD36 ligand-dependent signaling involves recruitment and activation of non-receptor tyrosine kinases (Src family), specific MAP kinases, and Vav family guanine nucleotide exchange factors; modulation of focal adhesion constituents; and generation of intracellular reactive oxygen species. CD36 is localized in cholesterol-rich membrane microdomains (lipid rafts) and interacts with tetraspanins and integrins.","method":"Biochemical signaling studies; co-immunoprecipitation; subcellular fractionation; genetic and pharmacological perturbation of signaling components","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — review summarizing replicated biochemical signaling findings from multiple labs; individual experiments Tier 2 quality","pmids":["19471024"],"is_preprint":false},{"year":2009,"finding":"CD36 mediates phagocytic internalization of Plasmodium falciparum-parasitized erythrocytes (PEs) by macrophages independently of TLR2 or IRAK4 signaling. Selective CD36 engagement does not by itself produce proinflammatory cytokines; however, TLR agonist pretreatment markedly enhances CD36-mediated particle uptake, indicating CD36 must cooperate with TLRs for cytokine responses.","method":"Antibody-induced CD36 endocytosis; phagocytosis assays with PEs in primary human and murine macrophages; TLR2/IRAK4-deficient macrophages; cytokine measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological approaches in primary cells with defined phenotypic readouts; multiple orthogonal methods","pmids":["19864601"],"is_preprint":false},{"year":2012,"finding":"CD36 regulates adipocyte lipolysis by modulating cAMP levels and PKA-dependent phosphorylation of hormone-sensitive lipase (HSL) and perilipin. CD36 knockdown decreased lipolysis induced by β-adrenergic, adenylyl cyclase, and PDE inhibitor stimulation, and this was partially mediated through the Src-ERK1/2 pathway. Isoproterenol-induced CD36 internalization was blocked by HSL inhibition, revealing feedback regulation of lipolysis via CD36 trafficking.","method":"siRNA knockdown in 3T3-L1 adipocytes; cAMP measurement; HSL and perilipin phosphorylation assays; CD36-null mice; plasma membrane-impermeable CD36 inhibitor (sulfo-N-succinimidyl oleate); live-cell CD36 trafficking assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, KO mouse, pharmacological inhibitor, phosphorylation assays, trafficking) in single rigorous study","pmids":["22815385"],"is_preprint":false},{"year":2012,"finding":"CD36 promotes adipocyte differentiation (adipogenesis) in vitro and in vivo; CD36 gene silencing impairs preadipocyte differentiation, reduces de novo fat pad formation in nude mice, and CD36-deficient mice have lower adipose tissue mass in diet-induced obesity.","method":"CD36 siRNA knockdown in 3T3-F442A preadipocytes; Oil Red O staining; adipogenic marker expression; in vivo fat pad formation assay in NUDE mice; nutritional obesity model in CD36 KO mice","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro KD and in vivo KO with multiple orthogonal readouts across models","pmids":["22507268"],"is_preprint":false},{"year":2018,"finding":"Endothelial cell (EC)-specific, but not parenchymal cell (myocyte/adipocyte)-specific, CD36 deletion acts as a gatekeeper for tissue fatty acid uptake. EC-CD36 KO mice had increased fasting plasma FAs, reduced radiolabeled long-chain FA uptake into heart, skeletal muscle, and brown adipose tissue (confirmed by [11C]palmitate PET), and improved glucose tolerance and insulin sensitivity on high-fat diet.","method":"Cell-specific Cre-lox deletion; radiolabeled FA uptake assays; [11C]palmitate PET imaging; plasma FA/TG measurements; glucose/insulin tolerance tests","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-specific KO with multiple in vivo readouts including PET imaging and metabolic phenotyping; orthogonal confirmation","pmids":["30047927"],"is_preprint":false},{"year":2018,"finding":"CD36 promotes insulin receptor (IR) tyrosine phosphorylation via functional interaction with Fyn kinase, and recruits p85 to enhance downstream insulin signaling. CD36 deletion in skeletal muscle reduces ceramide levels but impairs meal-associated glucose disposal. Pretreatment with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, while unsaturated fatty acids are neutral or stimulatory.","method":"Skeletal muscle-specific CD36 KO mice; primary human myotube CD36 depletion; co-immunoprecipitation of CD36 with IR; Fyn kinase phosphorylation assays; ceramide measurement; glucose disposal during meals","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing CD36-IR interaction, KO phenotype, Fyn kinase mechanistic assay, and fatty acid specificity demonstrated with multiple orthogonal methods","pmids":["29748289"],"is_preprint":false},{"year":2019,"finding":"CD36 mediates a mitochondrial metabolic switch in macrophages from oxidative phosphorylation to superoxide production in response to oxidized LDL. OxLDL via CD36 upregulates long-chain FA uptake and mitochondrial import effectors while downregulating FA oxidation and inhibiting ATP5A (an ETC component), leading to FA accumulation, mitochondrial structural changes, superoxide production, and NF-κB activation driving chronic inflammation.","method":"RNA sequencing; flow cytometry; 3H-palmitic acid uptake; lipidomics; confocal and electron microscopy; functional energetics (mitochondria-specific superoxide inhibition); NF-κB activation assays; Apoe-null high-fat diet mouse model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including metabolic flux, lipidomics, imaging, genetic model, and mechanistic inhibitor experiments in one study","pmids":["31625810"],"is_preprint":false},{"year":2020,"finding":"Fatty acid binding to CD36 activates the downstream kinase LYN, which phosphorylates DHHC5 (a palmitoyl acyltransferase) at Tyr91, inactivating it. CD36 then undergoes depalmitoylation by APT1 and recruits SYK kinase to phosphorylate JNK and VAV proteins, initiating caveolae-dependent endocytic uptake of fatty acids. Dynamic palmitoylation cycling (palmitoylation/depalmitoylation) is required for CD36-mediated FA uptake; blocking endocytosis by inhibiting APT1, LYN, or SYK abolishes CD36-dependent FA uptake and lipid droplet growth.","method":"Co-immunoprecipitation; kinase assays; site-specific phosphorylation analysis (DHHC5 Tyr91); APT1/LYN/SYK inhibition; caveolae-dependent internalization assays; palmitoylation state manipulation; high-fat-diet mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted signaling cascade with site-specific mutagenesis/phosphorylation mapping, multiple genetic and pharmacological perturbations, and in vivo validation","pmids":["32958780"],"is_preprint":false},{"year":2020,"finding":"CD36 signaling in platelets generates hydrogen peroxide flux that promotes cysteine sulfenylation of Src family kinases, activating them and lowering the threshold for platelet activation in dyslipidemia. Selective inhibition of cysteine sulfenylation with carbon nucleophiles inhibited CD36-mediated platelet aggregation and procoagulant phosphatidylserine externalization, and rescued enhanced arterial thrombosis in dyslipidemic mice.","method":"Carbon nucleophile-based cysteine sulfenic acid detection; CD36-blocking antibody; enzymatic H2O2 degradation; platelet aggregation assays; phosphatidylserine externalization assay; in vivo arterial thrombosis model in dyslipidemic mice","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct chemical biology approach identifying sulfenylation targets, validated pharmacologically and in vivo with multiple orthogonal methods","pmids":["32946569"],"is_preprint":false},{"year":2020,"finding":"Deubiquitinase UCHL1 stabilizes CD36 protein by removing K48-polyubiquitin chains from CD36, preventing its proteasomal degradation. UCHL1 inhibition or deletion increases K48-polyubiquitin on CD36, reduces CD36 protein (but not mRNA), decreases oxLDL uptake, and reduces foam cell formation.","method":"UCHL1 siRNA/inhibitor treatment; ubiquitination analysis (K48-polyubiquitin); co-immunoprecipitation; CD36 protein and mRNA quantification; lipid accumulation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, single lab with two orthogonal methods (genetic and pharmacological); CD36 mRNA vs protein discordance confirms post-translational mechanism","pmids":["32801299"],"is_preprint":false},{"year":2021,"finding":"Hepatocyte CD36 promotes de novo lipogenesis (DNL) by forming a complex with INSIG2 that disrupts the SCAP-INSIG2 interaction, thereby releasing SCAP to escort SREBP1 from ER to Golgi for processing and activation. CD36-knockout hepatocytes show reduced SREBP1 and downstream lipogenic enzymes (FASN, ACCα, ACLY), while CD36 overexpression stimulates insulin-mediated DNL.","method":"Hepatocyte-specific CD36 KO mice; co-immunoprecipitation; proximity ligation assay (INSIG2-SCAP-CD36 interaction); RNA sequencing; lipid deposition and DNL measurement; INSIG2-SCAP interaction rescue with 25-hydroxycholesterol/betulin","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP and proximity ligation defining molecular complex, KO mouse phenotype, mechanistic rescue with SCAP-INSIG stabilizers, multiple orthogonal methods","pmids":["34974159"],"is_preprint":false},{"year":2021,"finding":"A subset of Kupffer cells (KC2) expressing CD36 contributes to liver oxidative stress in obesity-associated hepatic steatosis. Targeted silencing of Cd36 specifically in KC2 reduces liver oxidative stress associated with obesity, demonstrating a cell-autonomous metabolic function of CD36 in this Kupffer cell subpopulation.","method":"High-dimensional single-cell profiling; KC2 depletion and targeted Cd36 silencing; oxidative stress measurement in diet-induced obesity mouse model","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted in vivo KD with defined phenotypic readout; single lab with two orthogonal perturbations","pmids":["34469775"],"is_preprint":false},{"year":2023,"finding":"CD36 binds to FSP1 (ferroptosis suppressor protein 1) and regulates its ubiquitination at K16 and K24, leading to FSP1 degradation and progression of ferroptosis in renal proximal tubular cells. CD36 deletion in mice increases ROS accumulation, ferroptosis activation, and acute kidney injury, identifying CD36 as a regulator of FSP1 stability.","method":"LC-MS/MS; co-immunoprecipitation; ubiquitination site mapping (K16, K24 of FSP1); CD36-null mice; cisplatin-induced AKI model","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mass spectrometry-based ubiquitination site mapping and in vivo KO model; single lab","pmids":["37588197"],"is_preprint":false},{"year":2023,"finding":"CD36 promotes blast migration and extramedullary dissemination in AML via its interaction with thrombospondin-1, not through lipid uptake. CD36 was dispensable for lipid uptake in AML blasts but was required for TSP-1-driven migration. CD36 inhibition reduced metastasis in xenograft models and prolonged survival of chemotherapy-treated mice.","method":"CD36 inhibition in xenograft mouse models; TSP-1 binding assays; lipid uptake assays (showing CD36 dispensable); patient cohort correlation","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft model with mechanistic dissection separating TSP-1-migration vs. lipid uptake function; single lab","pmids":["37327406"],"is_preprint":false},{"year":2024,"finding":"SELENOK (selenoprotein K) regulates CD36 palmitoylation through DHHC6, controlling CD36 localization to the microglial plasma membrane and thereby enabling Aβ phagocytosis. SELENOK deficiency reduces CD36 palmitoylation, impairs CD36 membrane localization, and inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD AD mice.","method":"In vivo 5xFAD mouse model with SELENOK KO/OE; DHHC6 palmitoylation assays; CD36 palmitoylation measurement in AD patient and mouse brains; microglial phagocytosis assays; Aβ quantification","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation assays with identified writer (DHHC6), in vivo KO/OE phenotype, human brain validation; single lab","pmids":["38320455"],"is_preprint":false},{"year":2025,"finding":"CD36 binds diverse large/polar small-molecule drugs and PROTACs and facilitates their cellular uptake via CD36-mediated EEA1/Rab5-positive early endosomal cascade. Chemical modification of PROTACs to enhance CD36 binding (via prodrug approach) markedly enhances their anti-tumor efficacy by augmenting permeability and solubility.","method":"Biotinylated chemical-probe target fishing; genetic knockdown/knockin of CD36; endosomal co-localization (EEA1/Rab5 markers); in vitro and in vivo PROTAC uptake and efficacy assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical probe-based target identification, genetic validation (KD/KI), endosomal pathway mapping, and in vivo efficacy with medicinal chemistry confirmation","pmids":["40250420"],"is_preprint":false},{"year":2023,"finding":"CD36 in cancer-associated fibroblasts (CAFs) mediates oxidized LDL uptake, triggering lipid peroxidation/p38/C/EBPs-dependent MIF expression. The secreted MIF recruits CD33+ myeloid-derived suppressor cells (MDSCs) in a MIF- and CD74-dependent manner to create an immunosuppressive tumor microenvironment. CD36 inhibition synergizes with anti-PD-1 immunotherapy in HCC models.","method":"Lineage-tracing; CD36 inhibitor + oxLDL uptake assays; lipid peroxidation assays; p38/C/EBP pathway analysis; MDSC recruitment assays; co-implantation in vivo HCC model; anti-PD-1 combination treatment","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway defined with signaling assays and in vivo co-implantation model; single lab with multiple orthogonal methods","pmids":["36878933"],"is_preprint":false},{"year":2015,"finding":"TSP-1 interaction with CD36 on podocytes mediates free fatty acid (FFA)-induced podocyte apoptosis via a TGF-β-independent mechanism. FFA stimulates TSP-1 expression via MAPK pathway activation; blocking TSP-1-CD36 binding with a peptide attenuated FFA-induced podocyte apoptosis. In vivo, both TSP1-deficient and CD36-deficient mice showed attenuated obesity-associated podocyte apoptosis and dysfunction.","method":"Peptide blockade of TSP1-CD36 binding; TSP1 KO and CD36 KO mouse diet-induced obesity models; podocyte apoptosis assays; MAPK pathway analysis; TGF-β independence confirmed","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — peptide blockade and two KO mouse models with defined apoptosis readout; single lab","pmids":["25835637"],"is_preprint":false},{"year":2020,"finding":"Endothelial CD36 deficiency prevents normal angiogenesis and vascular repair after ischemia. Oleic acid (OA) increases EC migration and wound healing in a CD36-dependent manner. CD36 knockdown abolished OA-induced increases in phospho-AMPK, and EC-specific CD36 KO mice had reduced blood flow recovery and reduced CD31/MMP9 upregulation post-hindlimb ischemia.","method":"siRNA and antisense oligonucleotide CD36 KD; EC migration/wound healing assays; transwell migration; phospho-AMPK measurement; EC-specific CD36 KO mice; laser Doppler imaging post-ischemia; CD31 and MMP9 expression","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro KD and in vivo EC-specific KO with functional angiogenesis and AMPK signaling readouts; single lab","pmids":["33437358"],"is_preprint":false},{"year":2016,"finding":"CD36 differentially regulates macrophage responses to smooth (S-LPS) versus rough (R-LPS) lipopolysaccharide. CD36 can substitute for CD14 in loading R-LPS onto TLR4/MD-2 enabling CD14-independent responses. CD36 promotes TRIF-dependent TLR4 signaling by facilitating TLR4/MD-2 endocytosis for both LPS chemotypes, while negatively regulating MyD88-dependent S-LPS signaling in the presence of serum by mediating internalization of S-LPS/CD14 complexes.","method":"CD14-deficient and CD36-deficient macrophages; LPS binding and TLR4/MD-2 loading assays; endocytosis assays; MyD88- and TRIF-dependent signaling measurement; serum/serum-free conditions","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO macrophages with multiple signaling pathway readouts and defined mechanistic distinctions; single lab","pmids":["27073833"],"is_preprint":false},{"year":2023,"finding":"CD36 is required for efficient megakaryocyte differentiation, proplatelet production, and normal platelet counts. CD36 deletion in mice results in thrombocytopenia, and patients with CD36 loss-of-function mutations exhibit thrombocytopenia and increased bleeding. Megakaryocyte PUFA-containing phospholipid accumulation is largely dependent on CD36-mediated fatty acid uptake.","method":"CD36 KO mice; dietary PUFA/saturated FA manipulation; platelet count measurement; lipidome analysis of megakaryocytes and platelets; human CD36 loss-of-function patient analysis","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse KO, human genetic validation, lipidomics, and dietary intervention with defined megakaryopoiesis and platelet production phenotype; replicated across species","pmids":["39195958"],"is_preprint":false}],"current_model":"CD36 is a multifunctional membrane glycoprotein that acts as a multiligand scavenger receptor and transporter: it directly binds collagen (mediating platelet adhesion), thrombospondin-1 (via a two-step CLESH-1/TSR-1 interaction to regulate anti-angiogenesis and cell migration), oxidized LDL (triggering Src-family kinase/MAP kinase/ROS-driven inflammatory signaling and NF-κB activation in macrophages), and long-chain fatty acids (which it internalizes via a dynamic palmitoylation-regulated, LYN-DHHC5-APT1-SYK-dependent caveolae-endocytic pathway); in the insulin signaling context CD36 interacts with the insulin receptor and promotes Fyn-mediated IR tyrosine phosphorylation; in hepatocytes it complexes with INSIG2 to disrupt SCAP-INSIG2 interaction and activate SREBP1-driven de novo lipogenesis; in platelets it generates H2O2-driven Src family kinase cysteine sulfenylation to lower the activation threshold; CD36 surface availability and stability are regulated by dynamic palmitoylation (via DHHC5/DHHC6/APT1), ubiquitination (stabilized by UCHL1), and translocation between intracellular depots and the plasma membrane; and it also mediates endocytic uptake of large polar drugs including PROTACs via an EEA1/Rab5 endosomal cascade."},"narrative":{"mechanistic_narrative":"CD36 is a heavily glycosylated integral membrane scavenger receptor that functions as a multiligand sensor and transporter linking extracellular lipids and matrix proteins to intracellular signaling and metabolism [PMID:2468669, PMID:19471024]. It engages structurally diverse ligands: collagen, where it mediates early platelet adhesion and activation [PMID:2468670]; thrombospondin-1 (TSP-1), through a two-step CLESH-1/TSR-1 interaction that drives endothelial anti-angiogenic responses and, in AML blasts, lipid-uptake-independent migration and dissemination [PMID:1381367, PMID:12957861, PMID:37327406]; oxidized LDL, which redirects macrophage mitochondrial metabolism toward superoxide production and NF-κB-driven inflammation [PMID:31625810]; and long-chain fatty acids, which it transports into muscle, adipose, and other tissues, acting at the endothelium as a gatekeeper for tissue fatty acid uptake [PMID:15294038, PMID:30047927]. Fatty acid uptake proceeds through a dynamic palmitoylation cycle: ligand binding activates LYN, which inactivates the palmitoyl acyltransferase DHHC5, permitting APT1-mediated depalmitoylation and SYK recruitment to initiate caveolae-dependent endocytosis [PMID:32958780]. CD36 surface availability and stability are set by this palmitoylation cycling (also via DHHC6/SELENOK) and by UCHL1-mediated removal of K48-polyubiquitin that prevents proteasomal degradation [PMID:32801299, PMID:38320455]. Through these activities CD36 couples lipid handling to metabolic and inflammatory programs: it enhances insulin receptor phosphorylation via Fyn [PMID:29748289], drives hepatocyte de novo lipogenesis by complexing with INSIG2 to free SCAP and activate SREBP1 [PMID:34974159], promotes adipogenesis and regulates adipocyte lipolysis through cAMP/PKA and Src-ERK signaling [PMID:22815385, PMID:22507268], and is required for megakaryocyte PUFA accumulation, proplatelet production, and normal platelet counts, with human loss-of-function mutations causing thrombocytopenia and bleeding [PMID:39195958]. In platelets, CD36 signaling generates H2O2 that sulfenylates Src-family kinase cysteines to lower the activation threshold in dyslipidemia [PMID:32946569]. CD36 also mediates phagocytic and endocytic internalization, taking up Plasmodium-infected erythrocytes and cooperating with TLRs [PMID:19864601, PMID:27073833], and routing large polar drugs and PROTACs through an EEA1/Rab5 endosomal cascade [PMID:40250420].","teleology":[{"year":1989,"claim":"Established CD36/GPIV as a defined cell-surface glycoprotein and its first ligand, answering what the molecule is and how it engages collagen during platelet adhesion.","evidence":"Protein purification, Edman sequencing, and carbohydrate analysis plus direct collagen binding and platelet aggregation assays","pmids":["2468669","2468670"],"confidence":"High","gaps":["Collagen-binding domain not mapped at residue level","Downstream platelet signaling from collagen engagement not defined"]},{"year":1992,"claim":"Resolved the molecular logic of CD36-thrombospondin-1 binding, showing a two-step conformational mechanism rather than a single-site interaction.","evidence":"Synthetic CD36 peptide competition and solid-phase TSP-1 binding with epitope mapping","pmids":["1381367"],"confidence":"High","gaps":["Functional consequence of TSP-1 binding not addressed in this study","No structural validation of the two-step model"]},{"year":2003,"claim":"Identified CD36 as the endothelial TSP-1 receptor mediating anti-angiogenic signaling via the CLESH-1/TSR-1 interface, extending TSP-1 binding to vascular biology.","evidence":"Domain structure-function analysis, competition binding, and in vivo angiogenesis models (review of primary work)","pmids":["12957861"],"confidence":"Medium","gaps":["Review summary rather than single primary dataset","Intracellular signaling from CLESH-1 engagement not detailed"]},{"year":2004,"claim":"Defined CD36 as a regulated fatty acid transporter, showing acute insulin/contraction-driven translocation from intracellular depots to the plasma membrane.","evidence":"Null/overexpression studies, subcellular fractionation, and radiolabeled FA uptake in muscle (review)","pmids":["15294038"],"confidence":"Medium","gaps":["Molecular machinery of translocation not identified","Direct fatty acid transport mechanism vs. facilitated uptake unresolved"]},{"year":2009,"claim":"Outlined the CD36 signaling apparatus—Src-family kinases, MAP kinases, Vav GEFs, and ROS within lipid rafts—linking ligand binding to intracellular cascades.","evidence":"Co-IP, fractionation, and genetic/pharmacological perturbation (review)","pmids":["19471024"],"confidence":"Medium","gaps":["Ligand-specific signaling specificity not delineated","Direct kinase recruitment mechanism unresolved"]},{"year":2009,"claim":"Showed CD36 mediates phagocytic uptake of parasitized erythrocytes but requires TLR cooperation for cytokine output, separating internalization from inflammatory signaling.","evidence":"Antibody-induced endocytosis and phagocytosis assays in TLR2/IRAK4-deficient primary macrophages","pmids":["19864601"],"confidence":"High","gaps":["Molecular basis of CD36-TLR cooperation not defined","Endocytic machinery for PE uptake not mapped"]},{"year":2012,"claim":"Connected CD36 to adipocyte biology, showing it both promotes adipogenesis and modulates lipolysis through cAMP/PKA and Src-ERK pathways with trafficking feedback.","evidence":"siRNA knockdown, CD36-null mice, pharmacological inhibitor, and phosphorylation/trafficking assays in adipocytes","pmids":["22815385","22507268"],"confidence":"High","gaps":["Direct link between FA transport and lipolytic signaling unresolved","How CD36 controls cAMP levels mechanistically unclear"]},{"year":2018,"claim":"Distinguished cell-type-specific CD36 functions: endothelial CD36 gates tissue FA uptake while muscle CD36 enhances insulin receptor signaling via Fyn.","evidence":"Cell-specific Cre-lox KO, [11C]palmitate PET, metabolic phenotyping, Co-IP of CD36 with IR, and Fyn kinase assays","pmids":["30047927","29748289"],"confidence":"High","gaps":["Mechanism by which endothelial CD36 transfers FA to parenchyma not defined","How fatty acid saturation tunes the CD36-Fyn-IR axis mechanistically unclear"]},{"year":2019,"claim":"Revealed that oxLDL-CD36 drives a macrophage mitochondrial switch from OXPHOS to superoxide production, mechanistically linking scavenger receptor uptake to chronic inflammation.","evidence":"RNA-seq, lipidomics, metabolic flux, imaging, and NF-κB assays in Apoe-null high-fat-diet model","pmids":["31625810"],"confidence":"High","gaps":["Direct effector linking CD36 to ATP5A inhibition not identified","Whether the switch is reversible in vivo unresolved"]},{"year":2020,"claim":"Defined the dynamic palmitoylation cycle as the engine of CD36 fatty acid uptake, with LYN-DHHC5-APT1-SYK controlling caveolae-dependent endocytosis.","evidence":"Co-IP, site-specific phosphorylation mapping (DHHC5 Tyr91), APT1/LYN/SYK inhibition, and in vivo validation","pmids":["32958780"],"confidence":"High","gaps":["Structural basis of palmitoylation-dependent conformational change unknown","How FA binding is transduced to LYN activation not resolved"]},{"year":2020,"claim":"Identified post-translational control of CD36 abundance—platelet redox signaling via Src sulfenylation and UCHL1 deubiquitination stabilizing CD36 against proteasomal degradation.","evidence":"Cysteine sulfenic acid chemical probes and platelet/thrombosis assays; UCHL1 KD/inhibition with K48-ubiquitin and protein/mRNA quantification","pmids":["32946569","32801299"],"confidence":"High","gaps":["UCHL1 finding rests on a single lab without reciprocal validation","E3 ligase placing K48 chains on CD36 not identified"]},{"year":2021,"claim":"Placed hepatocyte CD36 upstream of SREBP1-driven lipogenesis through an INSIG2-disrupting complex, and identified a CD36+ Kupffer cell subset driving steatosis-associated oxidative stress.","evidence":"Hepatocyte-specific KO, Co-IP, proximity ligation, and SCAP-INSIG rescue; single-cell profiling with targeted Cd36 silencing in KC2","pmids":["34974159","34469775"],"confidence":"High","gaps":["How a surface receptor accesses ER-resident INSIG2 not explained","KC2 oxidative stress mechanism only Medium-confidence"]},{"year":2023,"claim":"Extended CD36's reach to ubiquitin regulation of partner proteins and to lipid-uptake-independent functions, including FSP1 destabilization in ferroptosis and TSP-1-driven AML migration.","evidence":"LC-MS/MS, Co-IP, ubiquitination site mapping, and KO/xenograft models","pmids":["37588197","37327406","36878933"],"confidence":"Medium","gaps":["How CD36 directs ubiquitination of FSP1 mechanistically unclear","Each finding from a single lab without independent replication"]},{"year":2024,"claim":"Linked SELENOK and DHHC6 to CD36 palmitoylation in microglia, controlling membrane localization required for Aβ phagocytosis in an Alzheimer's model.","evidence":"SELENOK KO/OE, DHHC6 palmitoylation assays, microglial phagocytosis, and human brain validation in 5xFAD mice","pmids":["38320455"],"confidence":"Medium","gaps":["Single lab; reciprocal validation lacking","Relationship between DHHC6 and the DHHC5/APT1 cycle not integrated"]},{"year":2025,"claim":"Established CD36 as an uptake route for large polar small molecules and PROTACs through an EEA1/Rab5 endosomal cascade, opening a pharmacological exploitation of the receptor.","evidence":"Biotinylated probe target fishing, CD36 KD/KI, endosomal co-localization, and in vivo PROTAC efficacy with medicinal chemistry","pmids":["40250420"],"confidence":"High","gaps":["Binding determinants distinguishing drug cargo from lipid ligands not defined","Relationship to caveolae-dependent FA endocytosis route unclear"]},{"year":null,"claim":"How CD36's single receptor architecture selects among structurally unrelated ligands and routes each to distinct signaling, metabolic, endocytic, or ubiquitin-regulatory outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model coupling ligand identity to downstream pathway choice","How palmitoylation, ubiquitination, and redox modifications are coordinated in vivo unknown","Whether distinct internalization routes (caveolae vs. EEA1/Rab5) reflect distinct ligand classes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,9,12,25]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,6,11,20]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[4,9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,12,19]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,9,11,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,11,24]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,13,25]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,10,13]}],"complexes":[],"partners":["THBS1","INSIG2","FYN","LYN","SYK","UCHL1","AIFM2","INSR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16671","full_name":"Platelet glycoprotein 4","aliases":["Fatty acid translocase","FAT","Glycoprotein IIIb","GPIIIB","Leukocyte differentiation antigen CD36","PAS IV","PAS-4","Platelet collagen receptor","Platelet glycoprotein IV","GPIV","Thrombospondin receptor"],"length_aa":472,"mass_kda":53.1,"function":"Multifunctional glycoprotein that acts as a receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21395585, PubMed:21610069). Mechanistically, palmitoylated CD36 captures fatty acids on the cell surface, the binding of fatty acids activates downstream kinase LYN, which phosphorylates the palmitoyltransferase ZDHHC5 and inactivates it, resulting in the subsequent depalmitoylation of CD36, a step needed to initiate the endocytic process and delivery of fatty acids into the cell (PubMed:32958780). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellular calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thrombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). Involved in inducing apoptosis in podocytes in response to elevated free fatty acids, acting together with THBS1 (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211) (Microbial infection) Directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes and the internalization of particles independently of TLR signaling","subcellular_location":"Cell membrane; Membrane raft; Golgi apparatus; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/P16671/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD36","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/CD36","total_profiled":1310},"omim":[{"mim_id":"621264","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 1; FMAIT1","url":"https://www.omim.org/entry/621264"},{"mim_id":"621216","title":"PLAQUE-ENRICHED LONG NONCODING RNA IN ATHEROSCLEROTIC AND INFLAMMATORY BOWEL MACROPHAGE REGULATION; PELATON","url":"https://www.omim.org/entry/621216"},{"mim_id":"617626","title":"FIBROMATOSIS, GINGIVAL, 5; GINGF5","url":"https://www.omim.org/entry/617626"},{"mim_id":"611681","title":"A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 20; ADAMTS20","url":"https://www.omim.org/entry/611681"},{"mim_id":"611162","title":"MALARIA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/611162"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":1439.4},{"tissue":"breast","ntpm":534.4}],"url":"https://www.proteinatlas.org/search/CD36"},"hgnc":{"alias_symbol":["SCARB3","GPIV","FAT","GP4","GP3B","GPIIIB"],"prev_symbol":[]},"alphafold":{"accession":"P16671","domains":[{"cath_id":"-","chopping":"59-97_120-205_235-422","consensus_level":"medium","plddt":96.4436,"start":59,"end":422},{"cath_id":"1.10.287","chopping":"20-38_423-465","consensus_level":"medium","plddt":88.8542,"start":20,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16671","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16671-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16671-F1-predicted_aligned_error_v6.png","plddt_mean":93.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD36","jax_strain_url":"https://www.jax.org/strain/search?query=CD36"},"sequence":{"accession":"P16671","fasta_url":"https://rest.uniprot.org/uniprotkb/P16671.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16671/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16671"}},"corpus_meta":[{"pmid":"19471024","id":"PMC_19471024","title":"CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.","date":"2009","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/19471024","citation_count":973,"is_preprint":false},{"pmid":"2468670","id":"PMC_2468670","title":"Identification of glycoprotein IV (CD36) as a primary receptor for platelet-collagen adhesion.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2468670","citation_count":441,"is_preprint":false},{"pmid":"24903227","id":"PMC_24903227","title":"CD36, a scavenger receptor implicated in atherosclerosis.","date":"2014","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24903227","citation_count":420,"is_preprint":false},{"pmid":"32958780","id":"PMC_32958780","title":"CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32958780","citation_count":356,"is_preprint":false},{"pmid":"17442283","id":"PMC_17442283","title":"CD36 and macrophages in atherosclerosis.","date":"2007","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/17442283","citation_count":301,"is_preprint":false},{"pmid":"36878933","id":"PMC_36878933","title":"CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor.","date":"2023","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36878933","citation_count":300,"is_preprint":false},{"pmid":"31410189","id":"PMC_31410189","title":"CD36 tango in cancer: signaling pathways and functions.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31410189","citation_count":291,"is_preprint":false},{"pmid":"28919632","id":"PMC_28919632","title":"CD36 in chronic kidney disease: novel insights and therapeutic opportunities.","date":"2017","source":"Nature reviews. 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Malignancies.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32781778","citation_count":28,"is_preprint":false},{"pmid":"39195958","id":"PMC_39195958","title":"Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.","date":"2023","source":"Nature cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/39195958","citation_count":27,"is_preprint":false},{"pmid":"15790550","id":"PMC_15790550","title":"CD36: a multiligand molecule.","date":"2005","source":"Laboratory hematology : official publication of the International Society for Laboratory Hematology","url":"https://pubmed.ncbi.nlm.nih.gov/15790550","citation_count":27,"is_preprint":false},{"pmid":"29969695","id":"PMC_29969695","title":"Hypermethylated CD36 gene affected the progression of lung 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ccRCC.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36252650","citation_count":20,"is_preprint":false},{"pmid":"31909355","id":"PMC_31909355","title":"Hyperoxidized Albumin Modulates Platelets and Promotes Inflammation Through CD36 Receptor in Severe Alcoholic Hepatitis.","date":"2019","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/31909355","citation_count":20,"is_preprint":false},{"pmid":"30832758","id":"PMC_30832758","title":"CD36- and obesity-associated granulosa cells dysfunction.","date":"2019","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/30832758","citation_count":19,"is_preprint":false},{"pmid":"36557610","id":"PMC_36557610","title":"CD36-A Host Receptor Necessary for Malaria Parasites to Establish and Maintain Infection.","date":"2022","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/36557610","citation_count":19,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46335,"output_tokens":7572,"usd":0.126293,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17117,"output_tokens":5149,"usd":0.107155,"stage2_stop_reason":"end_turn"},"total_usd":0.233448,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"CD36 (GPIV) directly binds collagen Type I fibrils with high affinity (Kd ~0.34 nM) and mediates the early stages of platelet adhesion and activation in response to collagen, as demonstrated by competitive inhibition with purified GPIV and Fab fragments of anti-GPIV antibody blocking collagen-induced shape change, aggregation, and secretion.\",\n      \"method\": \"Direct binding assay of purified GPIV to collagen fibrils; competitive inhibition with purified GPIV and Fab fragments of polyclonal anti-GPIV antibody; platelet adhesion/aggregation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay with Kd measurement, competitive inhibition, multiple orthogonal functional assays in a single rigorous study\",\n      \"pmids\": [\"2468670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD36 (GPIV) is a heavily O- and N-glycosylated integral membrane glycoprotein (~88 kDa, 26% carbohydrate) with an N-terminal hydrophilic domain followed by a transmembrane domain, as determined by amino acid sequencing (first 36 residues via Edman degradation), carbohydrate composition analysis, and surface localization confirmed by flow cytometry and immunoprecipitation.\",\n      \"method\": \"Protein purification, Edman degradation N-terminal sequencing, carbohydrate composition analysis, flow cytometry, immunoprecipitation, radiolabeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical characterization with multiple orthogonal methods in a single dedicated study\",\n      \"pmids\": [\"2468669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD36-thrombospondin-1 (TSP-1) interaction occurs via a two-step mechanism: the CD36 sequence 139–155 binds first to TSP-1, inducing a conformational change that exposes a second high-affinity site on TSP-1 that then engages CD36 sequence 93–110. Peptide 139–155 augments rather than inhibits CD36-TSP binding, while peptide 93–110 blocks it.\",\n      \"method\": \"Synthetic CD36 peptide competition assays; solid-phase TSP binding; OKM5 epitope mapping; platelet aggregation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted binding with multiple peptides and orthogonal assays establishing a two-step mechanism in a single rigorous study\",\n      \"pmids\": [\"1381367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD36 is the endothelial cell receptor for thrombospondin-1 (TSP-1) and mediates its anti-angiogenic activity. Binding is mediated by the TSP type I repeat (TSR-1) domain of TSP-1 interacting with a conserved domain called CLESH-1 in CD36. Histidine-rich glycoprotein (HRGP) acts as a soluble decoy blocking TSP-1 binding to CD36, thereby inhibiting the anti-angiogenic response.\",\n      \"method\": \"Structure-function analysis of TSP-1 and CD36 domains; competition binding experiments; in vivo angiogenesis models\",\n      \"journal\": \"Frontiers in bioscience : a journal and virtual library\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function data and in vivo models but review article summarizing prior experiments; CLESH-1/TSR-1 interaction established in cited primary work\",\n      \"pmids\": [\"12957861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD36/FAT regulates fatty acid transport into cardiac and skeletal muscle cells; null mutation reduces FA uptake and metabolism while overexpression increases it. CD36 is also localized on the mitochondrial membrane and participates in FA transport across the mitochondrial membrane. Insulin and muscle contraction acutely translocate CD36 from an intracellular depot to the plasma membrane within minutes to increase FA transport.\",\n      \"method\": \"Genetic null mutation and overexpression studies; subcellular fractionation showing mitochondrial localization; radiolabeled FA uptake assays; insulin/contraction stimulation experiments in muscle\",\n      \"journal\": \"The Proceedings of the Nutrition Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/OE with defined FA uptake phenotype and subcellular localization by fractionation; single review summarizing replicated findings from multiple labs\",\n      \"pmids\": [\"15294038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD36 ligand-dependent signaling involves recruitment and activation of non-receptor tyrosine kinases (Src family), specific MAP kinases, and Vav family guanine nucleotide exchange factors; modulation of focal adhesion constituents; and generation of intracellular reactive oxygen species. CD36 is localized in cholesterol-rich membrane microdomains (lipid rafts) and interacts with tetraspanins and integrins.\",\n      \"method\": \"Biochemical signaling studies; co-immunoprecipitation; subcellular fractionation; genetic and pharmacological perturbation of signaling components\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — review summarizing replicated biochemical signaling findings from multiple labs; individual experiments Tier 2 quality\",\n      \"pmids\": [\"19471024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD36 mediates phagocytic internalization of Plasmodium falciparum-parasitized erythrocytes (PEs) by macrophages independently of TLR2 or IRAK4 signaling. Selective CD36 engagement does not by itself produce proinflammatory cytokines; however, TLR agonist pretreatment markedly enhances CD36-mediated particle uptake, indicating CD36 must cooperate with TLRs for cytokine responses.\",\n      \"method\": \"Antibody-induced CD36 endocytosis; phagocytosis assays with PEs in primary human and murine macrophages; TLR2/IRAK4-deficient macrophages; cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological approaches in primary cells with defined phenotypic readouts; multiple orthogonal methods\",\n      \"pmids\": [\"19864601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD36 regulates adipocyte lipolysis by modulating cAMP levels and PKA-dependent phosphorylation of hormone-sensitive lipase (HSL) and perilipin. CD36 knockdown decreased lipolysis induced by β-adrenergic, adenylyl cyclase, and PDE inhibitor stimulation, and this was partially mediated through the Src-ERK1/2 pathway. Isoproterenol-induced CD36 internalization was blocked by HSL inhibition, revealing feedback regulation of lipolysis via CD36 trafficking.\",\n      \"method\": \"siRNA knockdown in 3T3-L1 adipocytes; cAMP measurement; HSL and perilipin phosphorylation assays; CD36-null mice; plasma membrane-impermeable CD36 inhibitor (sulfo-N-succinimidyl oleate); live-cell CD36 trafficking assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, KO mouse, pharmacological inhibitor, phosphorylation assays, trafficking) in single rigorous study\",\n      \"pmids\": [\"22815385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD36 promotes adipocyte differentiation (adipogenesis) in vitro and in vivo; CD36 gene silencing impairs preadipocyte differentiation, reduces de novo fat pad formation in nude mice, and CD36-deficient mice have lower adipose tissue mass in diet-induced obesity.\",\n      \"method\": \"CD36 siRNA knockdown in 3T3-F442A preadipocytes; Oil Red O staining; adipogenic marker expression; in vivo fat pad formation assay in NUDE mice; nutritional obesity model in CD36 KO mice\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro KD and in vivo KO with multiple orthogonal readouts across models\",\n      \"pmids\": [\"22507268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endothelial cell (EC)-specific, but not parenchymal cell (myocyte/adipocyte)-specific, CD36 deletion acts as a gatekeeper for tissue fatty acid uptake. EC-CD36 KO mice had increased fasting plasma FAs, reduced radiolabeled long-chain FA uptake into heart, skeletal muscle, and brown adipose tissue (confirmed by [11C]palmitate PET), and improved glucose tolerance and insulin sensitivity on high-fat diet.\",\n      \"method\": \"Cell-specific Cre-lox deletion; radiolabeled FA uptake assays; [11C]palmitate PET imaging; plasma FA/TG measurements; glucose/insulin tolerance tests\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-specific KO with multiple in vivo readouts including PET imaging and metabolic phenotyping; orthogonal confirmation\",\n      \"pmids\": [\"30047927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD36 promotes insulin receptor (IR) tyrosine phosphorylation via functional interaction with Fyn kinase, and recruits p85 to enhance downstream insulin signaling. CD36 deletion in skeletal muscle reduces ceramide levels but impairs meal-associated glucose disposal. Pretreatment with saturated fatty acids suppresses CD36-Fyn enhancement of IR phosphorylation, while unsaturated fatty acids are neutral or stimulatory.\",\n      \"method\": \"Skeletal muscle-specific CD36 KO mice; primary human myotube CD36 depletion; co-immunoprecipitation of CD36 with IR; Fyn kinase phosphorylation assays; ceramide measurement; glucose disposal during meals\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing CD36-IR interaction, KO phenotype, Fyn kinase mechanistic assay, and fatty acid specificity demonstrated with multiple orthogonal methods\",\n      \"pmids\": [\"29748289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD36 mediates a mitochondrial metabolic switch in macrophages from oxidative phosphorylation to superoxide production in response to oxidized LDL. OxLDL via CD36 upregulates long-chain FA uptake and mitochondrial import effectors while downregulating FA oxidation and inhibiting ATP5A (an ETC component), leading to FA accumulation, mitochondrial structural changes, superoxide production, and NF-κB activation driving chronic inflammation.\",\n      \"method\": \"RNA sequencing; flow cytometry; 3H-palmitic acid uptake; lipidomics; confocal and electron microscopy; functional energetics (mitochondria-specific superoxide inhibition); NF-κB activation assays; Apoe-null high-fat diet mouse model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including metabolic flux, lipidomics, imaging, genetic model, and mechanistic inhibitor experiments in one study\",\n      \"pmids\": [\"31625810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fatty acid binding to CD36 activates the downstream kinase LYN, which phosphorylates DHHC5 (a palmitoyl acyltransferase) at Tyr91, inactivating it. CD36 then undergoes depalmitoylation by APT1 and recruits SYK kinase to phosphorylate JNK and VAV proteins, initiating caveolae-dependent endocytic uptake of fatty acids. Dynamic palmitoylation cycling (palmitoylation/depalmitoylation) is required for CD36-mediated FA uptake; blocking endocytosis by inhibiting APT1, LYN, or SYK abolishes CD36-dependent FA uptake and lipid droplet growth.\",\n      \"method\": \"Co-immunoprecipitation; kinase assays; site-specific phosphorylation analysis (DHHC5 Tyr91); APT1/LYN/SYK inhibition; caveolae-dependent internalization assays; palmitoylation state manipulation; high-fat-diet mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted signaling cascade with site-specific mutagenesis/phosphorylation mapping, multiple genetic and pharmacological perturbations, and in vivo validation\",\n      \"pmids\": [\"32958780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD36 signaling in platelets generates hydrogen peroxide flux that promotes cysteine sulfenylation of Src family kinases, activating them and lowering the threshold for platelet activation in dyslipidemia. Selective inhibition of cysteine sulfenylation with carbon nucleophiles inhibited CD36-mediated platelet aggregation and procoagulant phosphatidylserine externalization, and rescued enhanced arterial thrombosis in dyslipidemic mice.\",\n      \"method\": \"Carbon nucleophile-based cysteine sulfenic acid detection; CD36-blocking antibody; enzymatic H2O2 degradation; platelet aggregation assays; phosphatidylserine externalization assay; in vivo arterial thrombosis model in dyslipidemic mice\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct chemical biology approach identifying sulfenylation targets, validated pharmacologically and in vivo with multiple orthogonal methods\",\n      \"pmids\": [\"32946569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deubiquitinase UCHL1 stabilizes CD36 protein by removing K48-polyubiquitin chains from CD36, preventing its proteasomal degradation. UCHL1 inhibition or deletion increases K48-polyubiquitin on CD36, reduces CD36 protein (but not mRNA), decreases oxLDL uptake, and reduces foam cell formation.\",\n      \"method\": \"UCHL1 siRNA/inhibitor treatment; ubiquitination analysis (K48-polyubiquitin); co-immunoprecipitation; CD36 protein and mRNA quantification; lipid accumulation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, single lab with two orthogonal methods (genetic and pharmacological); CD36 mRNA vs protein discordance confirms post-translational mechanism\",\n      \"pmids\": [\"32801299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatocyte CD36 promotes de novo lipogenesis (DNL) by forming a complex with INSIG2 that disrupts the SCAP-INSIG2 interaction, thereby releasing SCAP to escort SREBP1 from ER to Golgi for processing and activation. CD36-knockout hepatocytes show reduced SREBP1 and downstream lipogenic enzymes (FASN, ACCα, ACLY), while CD36 overexpression stimulates insulin-mediated DNL.\",\n      \"method\": \"Hepatocyte-specific CD36 KO mice; co-immunoprecipitation; proximity ligation assay (INSIG2-SCAP-CD36 interaction); RNA sequencing; lipid deposition and DNL measurement; INSIG2-SCAP interaction rescue with 25-hydroxycholesterol/betulin\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP and proximity ligation defining molecular complex, KO mouse phenotype, mechanistic rescue with SCAP-INSIG stabilizers, multiple orthogonal methods\",\n      \"pmids\": [\"34974159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A subset of Kupffer cells (KC2) expressing CD36 contributes to liver oxidative stress in obesity-associated hepatic steatosis. Targeted silencing of Cd36 specifically in KC2 reduces liver oxidative stress associated with obesity, demonstrating a cell-autonomous metabolic function of CD36 in this Kupffer cell subpopulation.\",\n      \"method\": \"High-dimensional single-cell profiling; KC2 depletion and targeted Cd36 silencing; oxidative stress measurement in diet-induced obesity mouse model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted in vivo KD with defined phenotypic readout; single lab with two orthogonal perturbations\",\n      \"pmids\": [\"34469775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD36 binds to FSP1 (ferroptosis suppressor protein 1) and regulates its ubiquitination at K16 and K24, leading to FSP1 degradation and progression of ferroptosis in renal proximal tubular cells. CD36 deletion in mice increases ROS accumulation, ferroptosis activation, and acute kidney injury, identifying CD36 as a regulator of FSP1 stability.\",\n      \"method\": \"LC-MS/MS; co-immunoprecipitation; ubiquitination site mapping (K16, K24 of FSP1); CD36-null mice; cisplatin-induced AKI model\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mass spectrometry-based ubiquitination site mapping and in vivo KO model; single lab\",\n      \"pmids\": [\"37588197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD36 promotes blast migration and extramedullary dissemination in AML via its interaction with thrombospondin-1, not through lipid uptake. CD36 was dispensable for lipid uptake in AML blasts but was required for TSP-1-driven migration. CD36 inhibition reduced metastasis in xenograft models and prolonged survival of chemotherapy-treated mice.\",\n      \"method\": \"CD36 inhibition in xenograft mouse models; TSP-1 binding assays; lipid uptake assays (showing CD36 dispensable); patient cohort correlation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft model with mechanistic dissection separating TSP-1-migration vs. lipid uptake function; single lab\",\n      \"pmids\": [\"37327406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SELENOK (selenoprotein K) regulates CD36 palmitoylation through DHHC6, controlling CD36 localization to the microglial plasma membrane and thereby enabling Aβ phagocytosis. SELENOK deficiency reduces CD36 palmitoylation, impairs CD36 membrane localization, and inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD AD mice.\",\n      \"method\": \"In vivo 5xFAD mouse model with SELENOK KO/OE; DHHC6 palmitoylation assays; CD36 palmitoylation measurement in AD patient and mouse brains; microglial phagocytosis assays; Aβ quantification\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation assays with identified writer (DHHC6), in vivo KO/OE phenotype, human brain validation; single lab\",\n      \"pmids\": [\"38320455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD36 binds diverse large/polar small-molecule drugs and PROTACs and facilitates their cellular uptake via CD36-mediated EEA1/Rab5-positive early endosomal cascade. Chemical modification of PROTACs to enhance CD36 binding (via prodrug approach) markedly enhances their anti-tumor efficacy by augmenting permeability and solubility.\",\n      \"method\": \"Biotinylated chemical-probe target fishing; genetic knockdown/knockin of CD36; endosomal co-localization (EEA1/Rab5 markers); in vitro and in vivo PROTAC uptake and efficacy assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical probe-based target identification, genetic validation (KD/KI), endosomal pathway mapping, and in vivo efficacy with medicinal chemistry confirmation\",\n      \"pmids\": [\"40250420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD36 in cancer-associated fibroblasts (CAFs) mediates oxidized LDL uptake, triggering lipid peroxidation/p38/C/EBPs-dependent MIF expression. The secreted MIF recruits CD33+ myeloid-derived suppressor cells (MDSCs) in a MIF- and CD74-dependent manner to create an immunosuppressive tumor microenvironment. CD36 inhibition synergizes with anti-PD-1 immunotherapy in HCC models.\",\n      \"method\": \"Lineage-tracing; CD36 inhibitor + oxLDL uptake assays; lipid peroxidation assays; p38/C/EBP pathway analysis; MDSC recruitment assays; co-implantation in vivo HCC model; anti-PD-1 combination treatment\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway defined with signaling assays and in vivo co-implantation model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36878933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSP-1 interaction with CD36 on podocytes mediates free fatty acid (FFA)-induced podocyte apoptosis via a TGF-β-independent mechanism. FFA stimulates TSP-1 expression via MAPK pathway activation; blocking TSP-1-CD36 binding with a peptide attenuated FFA-induced podocyte apoptosis. In vivo, both TSP1-deficient and CD36-deficient mice showed attenuated obesity-associated podocyte apoptosis and dysfunction.\",\n      \"method\": \"Peptide blockade of TSP1-CD36 binding; TSP1 KO and CD36 KO mouse diet-induced obesity models; podocyte apoptosis assays; MAPK pathway analysis; TGF-β independence confirmed\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — peptide blockade and two KO mouse models with defined apoptosis readout; single lab\",\n      \"pmids\": [\"25835637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial CD36 deficiency prevents normal angiogenesis and vascular repair after ischemia. Oleic acid (OA) increases EC migration and wound healing in a CD36-dependent manner. CD36 knockdown abolished OA-induced increases in phospho-AMPK, and EC-specific CD36 KO mice had reduced blood flow recovery and reduced CD31/MMP9 upregulation post-hindlimb ischemia.\",\n      \"method\": \"siRNA and antisense oligonucleotide CD36 KD; EC migration/wound healing assays; transwell migration; phospho-AMPK measurement; EC-specific CD36 KO mice; laser Doppler imaging post-ischemia; CD31 and MMP9 expression\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro KD and in vivo EC-specific KO with functional angiogenesis and AMPK signaling readouts; single lab\",\n      \"pmids\": [\"33437358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD36 differentially regulates macrophage responses to smooth (S-LPS) versus rough (R-LPS) lipopolysaccharide. CD36 can substitute for CD14 in loading R-LPS onto TLR4/MD-2 enabling CD14-independent responses. CD36 promotes TRIF-dependent TLR4 signaling by facilitating TLR4/MD-2 endocytosis for both LPS chemotypes, while negatively regulating MyD88-dependent S-LPS signaling in the presence of serum by mediating internalization of S-LPS/CD14 complexes.\",\n      \"method\": \"CD14-deficient and CD36-deficient macrophages; LPS binding and TLR4/MD-2 loading assays; endocytosis assays; MyD88- and TRIF-dependent signaling measurement; serum/serum-free conditions\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO macrophages with multiple signaling pathway readouts and defined mechanistic distinctions; single lab\",\n      \"pmids\": [\"27073833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD36 is required for efficient megakaryocyte differentiation, proplatelet production, and normal platelet counts. CD36 deletion in mice results in thrombocytopenia, and patients with CD36 loss-of-function mutations exhibit thrombocytopenia and increased bleeding. Megakaryocyte PUFA-containing phospholipid accumulation is largely dependent on CD36-mediated fatty acid uptake.\",\n      \"method\": \"CD36 KO mice; dietary PUFA/saturated FA manipulation; platelet count measurement; lipidome analysis of megakaryocytes and platelets; human CD36 loss-of-function patient analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse KO, human genetic validation, lipidomics, and dietary intervention with defined megakaryopoiesis and platelet production phenotype; replicated across species\",\n      \"pmids\": [\"39195958\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD36 is a multifunctional membrane glycoprotein that acts as a multiligand scavenger receptor and transporter: it directly binds collagen (mediating platelet adhesion), thrombospondin-1 (via a two-step CLESH-1/TSR-1 interaction to regulate anti-angiogenesis and cell migration), oxidized LDL (triggering Src-family kinase/MAP kinase/ROS-driven inflammatory signaling and NF-κB activation in macrophages), and long-chain fatty acids (which it internalizes via a dynamic palmitoylation-regulated, LYN-DHHC5-APT1-SYK-dependent caveolae-endocytic pathway); in the insulin signaling context CD36 interacts with the insulin receptor and promotes Fyn-mediated IR tyrosine phosphorylation; in hepatocytes it complexes with INSIG2 to disrupt SCAP-INSIG2 interaction and activate SREBP1-driven de novo lipogenesis; in platelets it generates H2O2-driven Src family kinase cysteine sulfenylation to lower the activation threshold; CD36 surface availability and stability are regulated by dynamic palmitoylation (via DHHC5/DHHC6/APT1), ubiquitination (stabilized by UCHL1), and translocation between intracellular depots and the plasma membrane; and it also mediates endocytic uptake of large polar drugs including PROTACs via an EEA1/Rab5 endosomal cascade.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD36 is a heavily glycosylated integral membrane scavenger receptor that functions as a multiligand sensor and transporter linking extracellular lipids and matrix proteins to intracellular signaling and metabolism [#1, #5]. It engages structurally diverse ligands: collagen, where it mediates early platelet adhesion and activation [#0]; thrombospondin-1 (TSP-1), through a two-step CLESH-1/TSR-1 interaction that drives endothelial anti-angiogenic responses and, in AML blasts, lipid-uptake-independent migration and dissemination [#2, #3, #18]; oxidized LDL, which redirects macrophage mitochondrial metabolism toward superoxide production and NF-\\u03baB-driven inflammation [#11]; and long-chain fatty acids, which it transports into muscle, adipose, and other tissues, acting at the endothelium as a gatekeeper for tissue fatty acid uptake [#4, #9]. Fatty acid uptake proceeds through a dynamic palmitoylation cycle: ligand binding activates LYN, which inactivates the palmitoyl acyltransferase DHHC5, permitting APT1-mediated depalmitoylation and SYK recruitment to initiate caveolae-dependent endocytosis [#12]. CD36 surface availability and stability are set by this palmitoylation cycling (also via DHHC6/SELENOK) and by UCHL1-mediated removal of K48-polyubiquitin that prevents proteasomal degradation [#14, #19]. Through these activities CD36 couples lipid handling to metabolic and inflammatory programs: it enhances insulin receptor phosphorylation via Fyn [#10], drives hepatocyte de novo lipogenesis by complexing with INSIG2 to free SCAP and activate SREBP1 [#15], promotes adipogenesis and regulates adipocyte lipolysis through cAMP/PKA and Src-ERK signaling [#7, #8], and is required for megakaryocyte PUFA accumulation, proplatelet production, and normal platelet counts, with human loss-of-function mutations causing thrombocytopenia and bleeding [#25]. In platelets, CD36 signaling generates H2O2 that sulfenylates Src-family kinase cysteines to lower the activation threshold in dyslipidemia [#13]. CD36 also mediates phagocytic and endocytic internalization, taking up Plasmodium-infected erythrocytes and cooperating with TLRs [#6, #24], and routing large polar drugs and PROTACs through an EEA1/Rab5 endosomal cascade [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established CD36/GPIV as a defined cell-surface glycoprotein and its first ligand, answering what the molecule is and how it engages collagen during platelet adhesion.\",\n      \"evidence\": \"Protein purification, Edman sequencing, and carbohydrate analysis plus direct collagen binding and platelet aggregation assays\",\n      \"pmids\": [\"2468669\", \"2468670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Collagen-binding domain not mapped at residue level\", \"Downstream platelet signaling from collagen engagement not defined\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Resolved the molecular logic of CD36-thrombospondin-1 binding, showing a two-step conformational mechanism rather than a single-site interaction.\",\n      \"evidence\": \"Synthetic CD36 peptide competition and solid-phase TSP-1 binding with epitope mapping\",\n      \"pmids\": [\"1381367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of TSP-1 binding not addressed in this study\", \"No structural validation of the two-step model\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified CD36 as the endothelial TSP-1 receptor mediating anti-angiogenic signaling via the CLESH-1/TSR-1 interface, extending TSP-1 binding to vascular biology.\",\n      \"evidence\": \"Domain structure-function analysis, competition binding, and in vivo angiogenesis models (review of primary work)\",\n      \"pmids\": [\"12957861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review summary rather than single primary dataset\", \"Intracellular signaling from CLESH-1 engagement not detailed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined CD36 as a regulated fatty acid transporter, showing acute insulin/contraction-driven translocation from intracellular depots to the plasma membrane.\",\n      \"evidence\": \"Null/overexpression studies, subcellular fractionation, and radiolabeled FA uptake in muscle (review)\",\n      \"pmids\": [\"15294038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of translocation not identified\", \"Direct fatty acid transport mechanism vs. facilitated uptake unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Outlined the CD36 signaling apparatus—Src-family kinases, MAP kinases, Vav GEFs, and ROS within lipid rafts—linking ligand binding to intracellular cascades.\",\n      \"evidence\": \"Co-IP, fractionation, and genetic/pharmacological perturbation (review)\",\n      \"pmids\": [\"19471024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand-specific signaling specificity not delineated\", \"Direct kinase recruitment mechanism unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CD36 mediates phagocytic uptake of parasitized erythrocytes but requires TLR cooperation for cytokine output, separating internalization from inflammatory signaling.\",\n      \"evidence\": \"Antibody-induced endocytosis and phagocytosis assays in TLR2/IRAK4-deficient primary macrophages\",\n      \"pmids\": [\"19864601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CD36-TLR cooperation not defined\", \"Endocytic machinery for PE uptake not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected CD36 to adipocyte biology, showing it both promotes adipogenesis and modulates lipolysis through cAMP/PKA and Src-ERK pathways with trafficking feedback.\",\n      \"evidence\": \"siRNA knockdown, CD36-null mice, pharmacological inhibitor, and phosphorylation/trafficking assays in adipocytes\",\n      \"pmids\": [\"22815385\", \"22507268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between FA transport and lipolytic signaling unresolved\", \"How CD36 controls cAMP levels mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished cell-type-specific CD36 functions: endothelial CD36 gates tissue FA uptake while muscle CD36 enhances insulin receptor signaling via Fyn.\",\n      \"evidence\": \"Cell-specific Cre-lox KO, [11C]palmitate PET, metabolic phenotyping, Co-IP of CD36 with IR, and Fyn kinase assays\",\n      \"pmids\": [\"30047927\", \"29748289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which endothelial CD36 transfers FA to parenchyma not defined\", \"How fatty acid saturation tunes the CD36-Fyn-IR axis mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that oxLDL-CD36 drives a macrophage mitochondrial switch from OXPHOS to superoxide production, mechanistically linking scavenger receptor uptake to chronic inflammation.\",\n      \"evidence\": \"RNA-seq, lipidomics, metabolic flux, imaging, and NF-\\u03baB assays in Apoe-null high-fat-diet model\",\n      \"pmids\": [\"31625810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effector linking CD36 to ATP5A inhibition not identified\", \"Whether the switch is reversible in vivo unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the dynamic palmitoylation cycle as the engine of CD36 fatty acid uptake, with LYN-DHHC5-APT1-SYK controlling caveolae-dependent endocytosis.\",\n      \"evidence\": \"Co-IP, site-specific phosphorylation mapping (DHHC5 Tyr91), APT1/LYN/SYK inhibition, and in vivo validation\",\n      \"pmids\": [\"32958780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of palmitoylation-dependent conformational change unknown\", \"How FA binding is transduced to LYN activation not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified post-translational control of CD36 abundance—platelet redox signaling via Src sulfenylation and UCHL1 deubiquitination stabilizing CD36 against proteasomal degradation.\",\n      \"evidence\": \"Cysteine sulfenic acid chemical probes and platelet/thrombosis assays; UCHL1 KD/inhibition with K48-ubiquitin and protein/mRNA quantification\",\n      \"pmids\": [\"32946569\", \"32801299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"UCHL1 finding rests on a single lab without reciprocal validation\", \"E3 ligase placing K48 chains on CD36 not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed hepatocyte CD36 upstream of SREBP1-driven lipogenesis through an INSIG2-disrupting complex, and identified a CD36+ Kupffer cell subset driving steatosis-associated oxidative stress.\",\n      \"evidence\": \"Hepatocyte-specific KO, Co-IP, proximity ligation, and SCAP-INSIG rescue; single-cell profiling with targeted Cd36 silencing in KC2\",\n      \"pmids\": [\"34974159\", \"34469775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a surface receptor accesses ER-resident INSIG2 not explained\", \"KC2 oxidative stress mechanism only Medium-confidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended CD36's reach to ubiquitin regulation of partner proteins and to lipid-uptake-independent functions, including FSP1 destabilization in ferroptosis and TSP-1-driven AML migration.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, ubiquitination site mapping, and KO/xenograft models\",\n      \"pmids\": [\"37588197\", \"37327406\", \"36878933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD36 directs ubiquitination of FSP1 mechanistically unclear\", \"Each finding from a single lab without independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SELENOK and DHHC6 to CD36 palmitoylation in microglia, controlling membrane localization required for A\\u03b2 phagocytosis in an Alzheimer's model.\",\n      \"evidence\": \"SELENOK KO/OE, DHHC6 palmitoylation assays, microglial phagocytosis, and human brain validation in 5xFAD mice\",\n      \"pmids\": [\"38320455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation lacking\", \"Relationship between DHHC6 and the DHHC5/APT1 cycle not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CD36 as an uptake route for large polar small molecules and PROTACs through an EEA1/Rab5 endosomal cascade, opening a pharmacological exploitation of the receptor.\",\n      \"evidence\": \"Biotinylated probe target fishing, CD36 KD/KI, endosomal co-localization, and in vivo PROTAC efficacy with medicinal chemistry\",\n      \"pmids\": [\"40250420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding determinants distinguishing drug cargo from lipid ligands not defined\", \"Relationship to caveolae-dependent FA endocytosis route unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD36's single receptor architecture selects among structurally unrelated ligands and routes each to distinct signaling, metabolic, endocytic, or ubiquitin-regulatory outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model coupling ligand identity to downstream pathway choice\", \"How palmitoylation, ubiquitination, and redox modifications are coordinated in vivo unknown\", \"Whether distinct internalization routes (caveolae vs. EEA1/Rab5) reflect distinct ligand classes unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 9, 12, 25]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 6, 11, 20]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [4, 9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 12, 19]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 9, 11, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 11, 24]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 13, 25]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 10, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"THBS1\", \"INSIG2\", \"FYN\", \"LYN\", \"SYK\", \"UCHL1\", \"AIFM2\", \"INSR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}