{"gene":"AQP9","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1998,"finding":"AQP9 expressed in Xenopus oocytes functions as an osmotic water channel (7-fold increase in water permeability, low activation energy, mercury-inhibitable) and facilitates urea transport (4-fold increase), but does not increase glycerol permeability, distinguishing it from AQP3 and AQP7.","method":"Xenopus oocyte expression system, osmotic swelling assay, radiolabeled solute uptake","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in Xenopus oocytes with mercury inhibition controls, founding characterization paper replicated by subsequent studies","pmids":["9514918"],"is_preprint":false},{"year":2002,"finding":"AQP9 (and AQP7) transport arsenite [As(III)] and antimonite [Sb(III)]: AQP9 expressed in yeast fps1Δ cells restores metalloid sensitivity and enhances (73)As(III) and (125)Sb(III) uptake; AQP7 and AQP9 cRNA-injected Xenopus oocytes show increased (73)As(III) transport.","method":"Yeast complementation of fps1Δ strain, radiolabeled metalloid uptake in yeast and Xenopus oocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent functional assay systems (yeast complementation + Xenopus oocytes), replicated and extended by subsequent papers","pmids":["11972053"],"is_preprint":false},{"year":2003,"finding":"Purified rat AQP9 reconstituted in proteoliposomes exhibits mercury-inhibitable glycerol permeability (63-fold over background) and urea permeability (90-fold over background) at pH 7.5, but does not significantly increase beta-hydroxybutyrate or osmotic water permeability. AQP9 protein is localized to sinusoidal surfaces of hepatocyte plasma membranes, and its expression is induced up to 20-fold by fasting and elevated in streptozotocin-diabetic rats, returning to baseline with insulin treatment.","method":"Proteoliposome reconstitution with purified AQP9, stopped-flow light scattering, radiolabeled solute flux assays, confocal immunofluorescence, Western blot in fasted/diabetic rats","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein plus multiple solute permeability assays; localization and regulation validated in multiple physiological models","pmids":["12594337"],"is_preprint":false},{"year":2004,"finding":"AQP9 expression in K562 chronic myelogenous leukemia cells increases uptake of trivalent arsenic (As(III)) and antimonite (Sb(III)) and confers hypersensitivity to Trisenox (arsenic trioxide) and Sb(III). Vitamin D treatment of HL60 cells increases AQP9 expression and similarly confers metalloid hypersensitivity, demonstrating that AQP9 is the drug uptake transporter responsible for arsenic-based chemotherapy sensitivity.","method":"Stable transfection of AQP9 into K562 cells, cell viability assays, radiolabeled metalloid uptake, pharmacological induction with vitamin D","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic gain-of-function and pharmacological induction in two cell lines with uptake measurements and viability readouts; replicated concept from prior oocyte work","pmids":["15336539"],"is_preprint":false},{"year":2005,"finding":"Brain mitochondria express a short (~25 kDa) AQP9 isoform arising from alternative splicing, which is enriched in the inner mitochondrial membrane as shown by subcellular fractionation and immunogold electron microscopy. This isoform is present in astrocytes throughout the brain and in dopaminergic neurons of substantia nigra, ventral tegmental area, and arcuate nucleus.","method":"Subcellular fractionation, immunoblotting, immunogold electron microscopy, double-labeling with tyrosine hydroxylase, in situ hybridization","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-resolution localization with multiple orthogonal methods (fractionation + immunogold EM + double-labeling), single lab","pmids":["16126913"],"is_preprint":false},{"year":2007,"finding":"AQP9 knockout mice show markedly elevated plasma glycerol and triglycerides compared to wild-type, confirming AQP9's role as the primary hepatic entry channel for glycerol. Blood glucose was significantly lower in obese AQP9-knockout (Leprdb/Leprdb AQP9-/-) mice during fasting, indicating AQP9 is required for efficient hepatic glycerol utilization in gluconeogenesis. AQP9 protein was detected in hepatocytes, epididymis, vas deferens, and epidermis but not in brain.","method":"AQP9 knockout mouse phenotyping, plasma glycerol/triglyceride/glucose measurements, immunohistochemistry with multiple antibodies and knockout controls, oral glycerol tolerance test","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with definitive biochemical phenotype replicated across multiple metabolic challenges and genetic backgrounds","pmids":["17360690"],"is_preprint":false},{"year":2007,"finding":"AQP9 expression in RGC-5 retinal ganglion cells mediates cell volume regulation in response to hypotonic stress; the AQP9 inhibitor phloretin blocks hypotonic-induced cell swelling. AQP9 expression is upregulated by hypoxia and hypotonic shock, suggesting a role in energy balance as a glycerol-lactate channel in retinal ganglion neurons.","method":"Cell volume measurement, pharmacological inhibition with phloretin, Western blot and RT-PCR under hypoxia/hypotonic conditions in RGC-5 cells and primary RGCs","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition with phloretin supports volume regulation role; multiple conditions tested but single lab","pmids":["17337204"],"is_preprint":false},{"year":2007,"finding":"In streptozotocin-diabetic rats (low systemic insulin), AQP9 expression is selectively increased in catecholaminergic neurons of the brainstem. In brainstem slice cultures, 2 μM insulin application significantly decreases AQP9 protein levels within 6 h, demonstrating direct insulin-mediated regulation of brain AQP9 in catecholaminergic neurons.","method":"Immunocytochemistry, Western blot, brainstem slice culture with insulin treatment","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo model plus direct ex vivo insulin manipulation; single lab with two orthogonal approaches","pmids":["18053968"],"is_preprint":false},{"year":2009,"finding":"AQP9 in brain exists in tetrameric form (confirmed by blue native gel electrophoresis); the tetramer band is absent in AQP9 knockout brain and liver. Subpopulations of nigral neurons express AQP9 at both mRNA and protein levels; cortical cells including hilar hippocampal neurons contain AQP9 mRNA but no detectable AQP9 immunosignal.","method":"Blue native PAGE, real-time PCR, immunocytochemistry, in situ hybridization, all with AQP9 knockout controls","journal":"Journal of neuroscience research","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout-validated localization and biochemical characterization using multiple orthogonal methods","pmids":["19115411"],"is_preprint":false},{"year":2009,"finding":"Human AQP9 transports pentavalent methylated arsenicals MAs(V) and DMAs(V) in a pH-dependent manner (higher rate at pH 5.5 than neutral pH) in Xenopus oocytes. Hg(II) inhibits all four arsenic species transport; phloretin inhibits pentavalent MAs(V) and DMAs(V) but not trivalent As(III) and MAs(III), indicating distinct translocation mechanisms for trivalent vs. pentavalent arsenicals through AQP9.","method":"Xenopus oocyte expression, radiolabeled arsenic uptake at different pH, pharmacological inhibition with Hg(II), phloretin, FCCP, valinomycin, nigericin","journal":"Biometals","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional transport assay with multiple pharmacological probes discriminating mechanistic pathways; builds on replicated oocyte system","pmids":["19802720"],"is_preprint":false},{"year":2009,"finding":"CFTR co-localizes with AQP9 at the apical membrane of syncytiotrophoblast in normal placenta; CFTR expression decreases in preeclamptic placentas with loss of apical co-localization with AQP9. CFTR inhibitors reduce water uptake in normal placental explants, suggesting CFTR regulates AQP9 functionality.","method":"Western blot, immunohistochemistry, immunofluorescence co-localization, CFTR inhibitor functional water uptake assay in placental explants","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and pharmacological inhibition data from single lab; indirect evidence for regulation","pmids":["19481256"],"is_preprint":false},{"year":2012,"finding":"siRNA knockdown of AQP9 in cultured astrocytes decreases glycerol uptake and is associated with compensatory increase in glucose uptake and oxidative metabolism, confirming AQP9 as the primary glycerol transport pathway in astrocytes and demonstrating its role in astrocyte energy metabolism.","method":"AQP9 siRNA in astrocyte cultures, glycerol uptake assay, glucose uptake measurement, metabolic profiling","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific siRNA and functional metabolic readouts; single lab","pmids":["22842525"],"is_preprint":false},{"year":2013,"finding":"Site-directed mutagenesis of an intracellular binding site on AQP9 (identified by homology modeling and molecular dynamics/docking) alters sensitivity to small molecule inhibitors, validating the intracellular binding site as functionally relevant. Novel inhibitors with low micromolar IC50 identified by in silico screening targeting this site are active in mammalian cell water permeability assays.","method":"Homology modeling, molecular dynamics simulation, molecular docking, site-directed mutagenesis, mammalian cell water permeability assay","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus functional assay validates binding site; single lab with computational and experimental validation","pmids":["23448163"],"is_preprint":false},{"year":2014,"finding":"AQP9 and monocarboxylate transporter MCT2 co-immunoprecipitate from hippocampal neuron homogenates and co-localize in mitochondria of hippocampal neurons. Glutamate exposure increases AQP9 and MCT2 protein expression post-translationally (no mRNA change), and decreases glucose utilization, suggesting AQP9 facilitates alternative fuel (monocarboxylate) access to mitochondria.","method":"Co-immunoprecipitation, co-localization imaging, Western blot and RT-PCR before/after glutamate treatment, glucose utilization assay in primary hippocampal neurons","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus co-localization plus functional metabolic readout; single lab","pmids":["25161606"],"is_preprint":false},{"year":2018,"finding":"AQP9 is permeable to the parkinsonogenic toxin MPP+ as demonstrated by Xenopus oocyte uptake assay. Stable AQP9 expression in HEK cells increases their vulnerability to MPP+ and arsenite. AQP9 knockout in mice protects nigral dopaminergic neurons from MPP+ toxicity in organotypic midbrain slice cultures and in vivo intrastriatal injection models (48% reduction in TH+ cells in AQP9 KO vs. 67% in WT).","method":"Xenopus oocyte MPP+ uptake assay, stable HEK cell expression, cell viability, organotypic slice culture, intrastriatal MPP+ injection in AQP9 KO vs. WT mice, TH+ cell counting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal systems (oocyte, cell line, ex vivo slice, in vivo KO) with consistent results across labs","pmids":["29566083"],"is_preprint":false},{"year":2020,"finding":"AQP9 acts as an astrocyte-to-neuron lactate shuttle (ANLS) in concert with monocarboxylate transporters (MCTs) to support retinal ganglion cell (RGC) function and survival. AQP9 co-localizes with MCTs 1, 2, and 4 at the ganglion cell layer and co-immunoprecipitates with these MCTs in WT retina. Aqp9-null mice show greater RGC loss and reduced electroretinographic pSTR amplitude after optic nerve crush, reduced intraretinal lactate, and elevated glucose levels; glucose transporter GLUT1 expression is compensatorily increased.","method":"Aqp9 knockout mouse with optic nerve crush model, RGC density counting, electroretinography, co-immunoprecipitation of AQP9 with MCT1/2/4, immunolabeling, intraretinal metabolite measurement, MCT2 inhibitor injection","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple functional readouts, co-IP with MCTs, and metabolic substrate quantification; multiple orthogonal methods in a single rigorous study","pmids":["32748371"],"is_preprint":false},{"year":2022,"finding":"AQP9 transports lactate in macrophages: AQP9 overexpression in CHO cells increases lactate import rate; AQP9-/- macrophages and AQP9 knockdown RAW264.7 cells show reduced lactate transport. In the tumor microenvironment, AQP9-mediated lactate import drives M2-like macrophage polarization and VEGF production; AQP9-/- mice resist tumor growth and show suppressed M2 polarization in tumor tissue.","method":"AQP9 overexpression in CHO cells (lactate transport assay), AQP9-/- bone marrow-derived macrophage polarization assay, AQP9 knockdown in RAW264.7 cells, tumor allograft mouse model, VEGF ELISA","journal":"Biochemistry and biophysics reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function transport assay in CHO cells, loss-of-function in primary macrophages and cell line, and in vivo tumor model with consistent mechanistic findings","pmids":["35967760"],"is_preprint":false},{"year":2024,"finding":"AQP9 in macrophages transports glycerol intracellularly where it is metabolized to lysophosphatidic acid (LPA), activating the LPAR2 receptor and downstream Hippo pathway to promote expression of cytokines IL-23 and IL-1β. AQP9 blockade in macrophages decreases inflamed macrophage cytokine expression and enhances anti-TNF therapy response in a CD mouse model.","method":"Transcriptomic analysis, AQP9-specific inhibition in macrophages, cytokine expression (ELISA, Western blot), LPA metabolite measurement, LPAR2 pathway mechanistic studies, in vivo CD mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (glycerol→LPA→LPAR2→Hippo) defined in macrophages with in vitro and in vivo validation; single lab","pmids":["38583685"],"is_preprint":false},{"year":2025,"finding":"AQP9 knockdown in PMA-stimulated neutrophils suppresses JAK2-STAT3 pathway activation, reduces pyroptosis, and decreases NET formation, thereby reducing intestinal epithelial cell injury. Reactivation of JAK2-STAT3 or pyroptosis in AQP9-knockdown neutrophils restores NET formation and epithelial damage, placing AQP9 upstream of JAK2-STAT3-mediated pyroptosis in neutrophil-driven intestinal inflammation.","method":"siRNA knockdown of AQP9 in PMA-stimulated neutrophils, Western blot for JAK2-STAT3 pathway, ELISA for cytokines, immunofluorescence for NETs, co-culture with intestinal epithelial cells, CCK-8 and TUNEL assays, DSS-induced colitis mouse model","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue with pathway agonists plus in vivo model; single lab with multiple orthogonal methods","pmids":["41504039"],"is_preprint":false},{"year":2025,"finding":"Selective pharmacological blockade of AQP9 (with inhibitor RG100204) significantly impairs PBMC and neutrophil migration in response to LPS. Simultaneous inhibition of both AQP3 and AQP9 is required to impair monocyte phagocytosis of K. pneumoniae (at 60 min); individual AQP9 blockade alone does not affect bacterial killing.","method":"Specific AQP9 inhibitor (HTS13286 and RG100204) treatment of human PBMCs and neutrophils, transwell migration assay with/without LPS, phagocytosis assay with K. pneumoniae, bacterial killing assay, RT-qPCR, immunofluorescence","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with specific inhibitors and defined functional readouts in primary human cells; single lab","pmids":["40558507"],"is_preprint":false},{"year":2010,"finding":"hCG treatment of normal placental explants increases AQP9 protein expression in a concentration-dependent manner via cAMP pathways (mimicked by 8-Br-cAMP), and increases water uptake 1.6-fold; AQP9 localizes to both the apical membrane and cytoplasm of syncytiotrophoblast after treatment.","method":"Placental explant culture with recombinant hCG or 8-Br-cAMP, Western blot, immunofluorescence localization, water uptake assay","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological manipulation with functional water uptake readout and localization; single lab, two orthogonal approaches","pmids":["20220109"],"is_preprint":false},{"year":2011,"finding":"Insulin decreases AQP9 molecular expression in normal placental explants in a concentration-dependent manner; TNF-α pretreatment (which induces IRS phosphorylation and desensitizes insulin signaling) prevents insulin-induced AQP9 downregulation. Insulin treatment does not modify water uptake or its mercury sensitivity in placental explants, indicating AQP9 water permeability is independent of its expression level in this tissue.","method":"Placental explant culture with varying insulin concentrations, TNF-α pretreatment, Western blot for AQP9, water uptake assay with HgCl2 sensitivity","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological dissection of insulin/TNF-α regulation with multiple concentrations and functional readout; single lab","pmids":["22018417"],"is_preprint":false}],"current_model":"AQP9 is an aquaglyceroporin channel that facilitates transmembrane flux of water, glycerol, urea, monocarboxylates (including lactate), and metalloids (arsenite, antimonite, MPP+); in hepatocytes it serves as the primary entry route for blood glycerol enabling gluconeogenesis (regulated inversely by insulin); in macrophages it imports lactate and glycerol to drive metabolic reprogramming and inflammatory cytokine production via LPA–LPAR2–Hippo signaling; in brain it localizes to the inner mitochondrial membrane of astrocytes and dopaminergic neurons where it participates in an astrocyte-to-neuron lactate shuttle (in complex with MCT1/2/4); in leukocytes it is required for cell migration and, via its metalloid permeability, determines sensitivity to arsenic-based therapeutics; and its activity can be modulated by small molecules targeting an intracellular binding site."},"narrative":{"mechanistic_narrative":"AQP9 is an aquaglyceroporin channel that mediates mercury-inhibitable transmembrane flux of water, urea, glycerol, monocarboxylates such as lactate, and metalloids, functioning as a multi-substrate conduit that couples solute permeability to tissue-specific metabolic and immune programs [PMID:9514918, PMID:12594337, PMID:35967760]. Reconstitution of purified protein established robust glycerol and urea permeability, and in the liver AQP9 localizes to hepatocyte sinusoidal membranes where its expression is induced by fasting and diabetes and reversed by insulin [PMID:12594337]; knockout mice exhibit elevated plasma glycerol and triglycerides with impaired fasting glucose, confirming AQP9 as the primary hepatic glycerol entry route for gluconeogenesis [PMID:17360690]. Beyond water and glycerol, AQP9 transports trivalent and pentavalent arsenicals and antimonite, and this metalloid permeability makes it the uptake transporter that determines cellular sensitivity to arsenic-based chemotherapeutics [PMID:11972053, PMID:15336539, PMID:19802720]; the same channel imports the parkinsonogenic toxin MPP+, such that AQP9 loss protects nigral dopaminergic neurons from MPP+ toxicity [PMID:29566083]. In the nervous system a short mitochondrial isoform is enriched in the inner mitochondrial membrane of astrocytes and dopaminergic neurons, where AQP9 supplies glycerol and supports monocarboxylate metabolism, physically associating with monocarboxylate transporters MCT1/2/4 to operate an astrocyte-to-neuron lactate shuttle required for retinal ganglion cell survival [PMID:16126913, PMID:22842525, PMID:32748371]. In innate immune cells AQP9 drives metabolic reprogramming and inflammation: lactate import promotes M2-like macrophage polarization and VEGF production, intracellular glycerol is converted to lysophosphatidic acid that activates LPAR2–Hippo signaling to induce IL-23 and IL-1β, and AQP9 is required for leukocyte migration and neutrophil JAK2-STAT3-driven pyroptosis and NET formation [PMID:35967760, PMID:38583685, PMID:41504039, PMID:40558507]. AQP9 assembles as a homotetramer and possesses a functionally validated intracellular small-molecule binding site exploited for inhibitor development [PMID:19115411, PMID:23448163].","teleology":[{"year":1998,"claim":"Established the founding channel identity of AQP9 by showing it conducts water and urea but, in the initial characterization, not glycerol, placing it among the aquaporins.","evidence":"Xenopus oocyte osmotic swelling and radiolabeled solute uptake assays","pmids":["9514918"],"confidence":"High","gaps":["Glycerol permeability not detected here, later contradicted by reconstitution","No structural basis for selectivity","Physiological tissue role not addressed"]},{"year":2002,"claim":"Showed AQP9 conducts the metalloids arsenite and antimonite, revealing a toxicologically important substrate class beyond classic small solutes.","evidence":"Yeast fps1Δ complementation and radiolabeled metalloid uptake in yeast and Xenopus oocytes","pmids":["11972053"],"confidence":"High","gaps":["Translocation mechanism for metalloids not defined","In vivo relevance to arsenic handling not yet tested"]},{"year":2003,"claim":"Reconstitution of purified protein resolved AQP9 as a high-capacity glycerol/urea channel and tied it to hepatic glycerol uptake regulated by fasting and insulin.","evidence":"Proteoliposome reconstitution, stopped-flow flux assays, hepatocyte immunolocalization, fasted/diabetic rat Western blots","pmids":["12594337"],"confidence":"High","gaps":["Causal requirement in gluconeogenesis not yet shown by genetics","Mechanism of insulin-dependent expression control unresolved"]},{"year":2004,"claim":"Demonstrated AQP9 is the drug-uptake transporter that confers sensitivity to arsenic trioxide chemotherapy, linking its metalloid permeability to therapeutic outcome.","evidence":"Stable AQP9 transfection in K562 cells, vitamin D induction in HL60, metalloid uptake and viability assays","pmids":["15336539"],"confidence":"High","gaps":["Endogenous AQP9 regulation in patient leukemia cells not addressed","Resistance mechanisms not explored"]},{"year":2005,"claim":"Identified a short alternatively spliced AQP9 isoform enriched in the inner mitochondrial membrane of astrocytes and dopaminergic neurons, defining a distinct subcellular pool.","evidence":"Subcellular fractionation, immunogold EM, tyrosine hydroxylase double-labeling, in situ hybridization","pmids":["16126913"],"confidence":"Medium","gaps":["Single lab; brain AQP9 expression later disputed by knockout-validated studies","Transport function of the mitochondrial isoform not measured"]},{"year":2007,"claim":"Genetic knockout proved AQP9 is the primary hepatic glycerol entry channel required for fasting gluconeogenesis, converting the correlative liver data into a causal role.","evidence":"AQP9 knockout mouse metabolic phenotyping, plasma glycerol/triglyceride/glucose, glycerol tolerance test, immunohistochemistry","pmids":["17360690"],"confidence":"High","gaps":["Brain AQP9 not detected here, conflicting with the mitochondrial isoform report","Compensatory glycerol routes not quantified"]},{"year":2007,"claim":"Connected AQP9 to volume regulation and energy balance in retinal neurons, and showed insulin directly downregulates brain AQP9 in catecholaminergic neurons.","evidence":"Phloretin inhibition and volume assays in RGC-5 cells; STZ-diabetic rats and insulin-treated brainstem slice cultures","pmids":["17337204","18053968"],"confidence":"Medium","gaps":["Single-lab pharmacology for the volume role","Signaling link between insulin and AQP9 turnover not defined"]},{"year":2009,"claim":"Defined AQP9 quaternary structure as a homotetramer with knockout-validated brain expression and refined metalloid handling by distinguishing trivalent from pentavalent arsenical pathways.","evidence":"Blue native PAGE with KO controls, real-time PCR, in situ hybridization; pH-dependent arsenic uptake with Hg(II)/phloretin discrimination in oocytes","pmids":["19115411","19802720"],"confidence":"High","gaps":["mRNA-protein discordance in cortical neurons unexplained","Atomic structure of the pore not determined"]},{"year":2012,"claim":"Loss-of-function in astrocytes confirmed AQP9 as the dominant glycerol uptake pathway whose loss forces a compensatory shift to glucose oxidation.","evidence":"AQP9 siRNA in astrocyte cultures with glycerol/glucose uptake and metabolic profiling","pmids":["22842525"],"confidence":"Medium","gaps":["Single lab","Link to neuronal fueling not tested in this study"]},{"year":2013,"claim":"Validated a functionally relevant intracellular small-molecule binding site, enabling rational AQP9 inhibitor design.","evidence":"Homology modeling, molecular dynamics/docking, site-directed mutagenesis, mammalian water permeability assays","pmids":["23448163"],"confidence":"Medium","gaps":["No experimental structure of the inhibitor complex","Selectivity over other aquaglyceroporins not fully resolved"]},{"year":2014,"claim":"Showed AQP9 physically partners with MCT2 at neuronal mitochondria and is co-upregulated post-translationally to provide monocarboxylate fuel access.","evidence":"Co-immunoprecipitation, co-localization imaging, glutamate-treated hippocampal neuron metabolic assays","pmids":["25161606"],"confidence":"Medium","gaps":["Single lab; direct AQP9 lactate transport not measured here","Mechanism of post-translational co-regulation unknown"]},{"year":2018,"claim":"Established AQP9 as the conduit for MPP+ entry into dopaminergic neurons, mechanistically linking its permeability to selective neurotoxin vulnerability.","evidence":"Oocyte MPP+ uptake, HEK expression, organotypic midbrain slices, and intrastriatal MPP+ injection in AQP9 KO vs WT mice","pmids":["29566083"],"confidence":"High","gaps":["Relevance to idiopathic Parkinson's disease not established","Protection incomplete, implying parallel uptake routes"]},{"year":2020,"claim":"Demonstrated AQP9 operates within an astrocyte-to-neuron lactate shuttle in complex with MCT1/2/4 to sustain retinal ganglion cell survival under injury.","evidence":"Aqp9 KO with optic nerve crush, RGC counting, electroretinography, co-IP with MCT1/2/4, intraretinal metabolite quantification, MCT2 inhibition","pmids":["32748371"],"confidence":"High","gaps":["Direct lactate flux through AQP9 versus regulatory MCT scaffolding not separated","Generalizability beyond retina untested"]},{"year":2022,"claim":"Showed AQP9-mediated lactate import drives M2 macrophage polarization and VEGF production, implicating it in tumor microenvironment immunometabolism.","evidence":"CHO overexpression lactate transport, AQP9-/- and knockdown macrophage polarization, tumor allograft model, VEGF ELISA","pmids":["35967760"],"confidence":"High","gaps":["Downstream signaling from lactate to polarization not fully mapped","Contribution relative to MCT lactate import not quantified"]},{"year":2024,"claim":"Defined a glycerol→LPA→LPAR2→Hippo axis through which macrophage AQP9 promotes inflammatory cytokine expression, providing a therapeutic rationale in Crohn's disease.","evidence":"Transcriptomics, AQP9 inhibition, LPA measurement, LPAR2/Hippo mechanistic studies, anti-TNF CD mouse model","pmids":["38583685"],"confidence":"Medium","gaps":["Single lab","Enzymatic steps converting glycerol to LPA not detailed"]},{"year":2025,"claim":"Placed AQP9 upstream of neutrophil JAK2-STAT3-driven pyroptosis and NET formation and confirmed its requirement for LPS-driven leukocyte migration.","evidence":"AQP9 siRNA in PMA-stimulated neutrophils with pathway rescue, DSS colitis model; RG100204/HTS13286 inhibition with migration and phagocytosis assays in human PBMCs/neutrophils","pmids":["41504039","40558507"],"confidence":"Medium","gaps":["Single labs; how AQP9 permeability activates JAK2-STAT3 not mechanistically resolved","Phagocytosis effect requires co-inhibition with AQP3, indicating redundancy"]},{"year":null,"claim":"How a single channel's substrate flux is selectively decoded into divergent outcomes (gluconeogenesis, neuronal fueling, metalloid toxicity, distinct inflammatory programs) and the atomic basis of its pore and inhibitor binding remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental high-resolution structure in the corpus","Tissue-specific regulation of substrate preference not mechanistically explained","Direct lactate transport contribution versus MCT scaffolding not cleanly dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,3,9,14,16]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[2,5,11,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,10,20]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,5,11,16]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,9,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,17,18,19]}],"complexes":[],"partners":["MCT2","MCT1","MCT4","CFTR","LPAR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14520","full_name":"Aquaporin-7","aliases":["Aquaglyceroporin-7","Aquaporin adipose","AQPap","Aquaporin-7-like"],"length_aa":342,"mass_kda":37.2,"function":"Aquaglyceroporins form homotetrameric transmembrane channels, with each monomer independently mediating glycerol and water transport across the plasma membrane along their osmotic gradient (PubMed:11952783, PubMed:30420639, PubMed:30423801, PubMed:36737436, PubMed:9405233). Could also be permeable to urea (PubMed:9405233). Mediates the efflux of glycerol, formed upon triglyceride hydrolysis, to avoid its accumulation in adipocytes and to make it available to other tissues. In the kidney, mediates the reabsorption of glycerol, preventing its loss in urine, again participating to energy homeostasis. In pancreatic beta cells, it also mediates the efflux of glycerol, regulating its intracellular levels (By similarity)","subcellular_location":"Cell membrane; Cytoplasmic vesicle membrane; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/O14520/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AQP9","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AQP9","total_profiled":1310},"omim":[{"mim_id":"606578","title":"AQUAPORIN 10; AQP10","url":"https://www.omim.org/entry/606578"},{"mim_id":"602974","title":"AQUAPORIN 7; AQP7","url":"https://www.omim.org/entry/602974"},{"mim_id":"602914","title":"AQUAPORIN 9; AQP9","url":"https://www.omim.org/entry/602914"},{"mim_id":"107776","title":"AQUAPORIN 1; AQP1","url":"https://www.omim.org/entry/107776"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in 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expression system, osmotic swelling assay, radiolabeled solute uptake\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in Xenopus oocytes with mercury inhibition controls, founding characterization paper replicated by subsequent studies\",\n      \"pmids\": [\"9514918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AQP9 (and AQP7) transport arsenite [As(III)] and antimonite [Sb(III)]: AQP9 expressed in yeast fps1Δ cells restores metalloid sensitivity and enhances (73)As(III) and (125)Sb(III) uptake; AQP7 and AQP9 cRNA-injected Xenopus oocytes show increased (73)As(III) transport.\",\n      \"method\": \"Yeast complementation of fps1Δ strain, radiolabeled metalloid uptake in yeast and Xenopus oocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent functional assay systems (yeast complementation + Xenopus oocytes), replicated and extended by subsequent papers\",\n      \"pmids\": [\"11972053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Purified rat AQP9 reconstituted in proteoliposomes exhibits mercury-inhibitable glycerol permeability (63-fold over background) and urea permeability (90-fold over background) at pH 7.5, but does not significantly increase beta-hydroxybutyrate or osmotic water permeability. AQP9 protein is localized to sinusoidal surfaces of hepatocyte plasma membranes, and its expression is induced up to 20-fold by fasting and elevated in streptozotocin-diabetic rats, returning to baseline with insulin treatment.\",\n      \"method\": \"Proteoliposome reconstitution with purified AQP9, stopped-flow light scattering, radiolabeled solute flux assays, confocal immunofluorescence, Western blot in fasted/diabetic rats\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein plus multiple solute permeability assays; localization and regulation validated in multiple physiological models\",\n      \"pmids\": [\"12594337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AQP9 expression in K562 chronic myelogenous leukemia cells increases uptake of trivalent arsenic (As(III)) and antimonite (Sb(III)) and confers hypersensitivity to Trisenox (arsenic trioxide) and Sb(III). Vitamin D treatment of HL60 cells increases AQP9 expression and similarly confers metalloid hypersensitivity, demonstrating that AQP9 is the drug uptake transporter responsible for arsenic-based chemotherapy sensitivity.\",\n      \"method\": \"Stable transfection of AQP9 into K562 cells, cell viability assays, radiolabeled metalloid uptake, pharmacological induction with vitamin D\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic gain-of-function and pharmacological induction in two cell lines with uptake measurements and viability readouts; replicated concept from prior oocyte work\",\n      \"pmids\": [\"15336539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Brain mitochondria express a short (~25 kDa) AQP9 isoform arising from alternative splicing, which is enriched in the inner mitochondrial membrane as shown by subcellular fractionation and immunogold electron microscopy. This isoform is present in astrocytes throughout the brain and in dopaminergic neurons of substantia nigra, ventral tegmental area, and arcuate nucleus.\",\n      \"method\": \"Subcellular fractionation, immunoblotting, immunogold electron microscopy, double-labeling with tyrosine hydroxylase, in situ hybridization\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-resolution localization with multiple orthogonal methods (fractionation + immunogold EM + double-labeling), single lab\",\n      \"pmids\": [\"16126913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AQP9 knockout mice show markedly elevated plasma glycerol and triglycerides compared to wild-type, confirming AQP9's role as the primary hepatic entry channel for glycerol. Blood glucose was significantly lower in obese AQP9-knockout (Leprdb/Leprdb AQP9-/-) mice during fasting, indicating AQP9 is required for efficient hepatic glycerol utilization in gluconeogenesis. AQP9 protein was detected in hepatocytes, epididymis, vas deferens, and epidermis but not in brain.\",\n      \"method\": \"AQP9 knockout mouse phenotyping, plasma glycerol/triglyceride/glucose measurements, immunohistochemistry with multiple antibodies and knockout controls, oral glycerol tolerance test\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with definitive biochemical phenotype replicated across multiple metabolic challenges and genetic backgrounds\",\n      \"pmids\": [\"17360690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AQP9 expression in RGC-5 retinal ganglion cells mediates cell volume regulation in response to hypotonic stress; the AQP9 inhibitor phloretin blocks hypotonic-induced cell swelling. AQP9 expression is upregulated by hypoxia and hypotonic shock, suggesting a role in energy balance as a glycerol-lactate channel in retinal ganglion neurons.\",\n      \"method\": \"Cell volume measurement, pharmacological inhibition with phloretin, Western blot and RT-PCR under hypoxia/hypotonic conditions in RGC-5 cells and primary RGCs\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition with phloretin supports volume regulation role; multiple conditions tested but single lab\",\n      \"pmids\": [\"17337204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In streptozotocin-diabetic rats (low systemic insulin), AQP9 expression is selectively increased in catecholaminergic neurons of the brainstem. In brainstem slice cultures, 2 μM insulin application significantly decreases AQP9 protein levels within 6 h, demonstrating direct insulin-mediated regulation of brain AQP9 in catecholaminergic neurons.\",\n      \"method\": \"Immunocytochemistry, Western blot, brainstem slice culture with insulin treatment\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo model plus direct ex vivo insulin manipulation; single lab with two orthogonal approaches\",\n      \"pmids\": [\"18053968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AQP9 in brain exists in tetrameric form (confirmed by blue native gel electrophoresis); the tetramer band is absent in AQP9 knockout brain and liver. Subpopulations of nigral neurons express AQP9 at both mRNA and protein levels; cortical cells including hilar hippocampal neurons contain AQP9 mRNA but no detectable AQP9 immunosignal.\",\n      \"method\": \"Blue native PAGE, real-time PCR, immunocytochemistry, in situ hybridization, all with AQP9 knockout controls\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout-validated localization and biochemical characterization using multiple orthogonal methods\",\n      \"pmids\": [\"19115411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human AQP9 transports pentavalent methylated arsenicals MAs(V) and DMAs(V) in a pH-dependent manner (higher rate at pH 5.5 than neutral pH) in Xenopus oocytes. Hg(II) inhibits all four arsenic species transport; phloretin inhibits pentavalent MAs(V) and DMAs(V) but not trivalent As(III) and MAs(III), indicating distinct translocation mechanisms for trivalent vs. pentavalent arsenicals through AQP9.\",\n      \"method\": \"Xenopus oocyte expression, radiolabeled arsenic uptake at different pH, pharmacological inhibition with Hg(II), phloretin, FCCP, valinomycin, nigericin\",\n      \"journal\": \"Biometals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional transport assay with multiple pharmacological probes discriminating mechanistic pathways; builds on replicated oocyte system\",\n      \"pmids\": [\"19802720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CFTR co-localizes with AQP9 at the apical membrane of syncytiotrophoblast in normal placenta; CFTR expression decreases in preeclamptic placentas with loss of apical co-localization with AQP9. CFTR inhibitors reduce water uptake in normal placental explants, suggesting CFTR regulates AQP9 functionality.\",\n      \"method\": \"Western blot, immunohistochemistry, immunofluorescence co-localization, CFTR inhibitor functional water uptake assay in placental explants\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and pharmacological inhibition data from single lab; indirect evidence for regulation\",\n      \"pmids\": [\"19481256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"siRNA knockdown of AQP9 in cultured astrocytes decreases glycerol uptake and is associated with compensatory increase in glucose uptake and oxidative metabolism, confirming AQP9 as the primary glycerol transport pathway in astrocytes and demonstrating its role in astrocyte energy metabolism.\",\n      \"method\": \"AQP9 siRNA in astrocyte cultures, glycerol uptake assay, glucose uptake measurement, metabolic profiling\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific siRNA and functional metabolic readouts; single lab\",\n      \"pmids\": [\"22842525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Site-directed mutagenesis of an intracellular binding site on AQP9 (identified by homology modeling and molecular dynamics/docking) alters sensitivity to small molecule inhibitors, validating the intracellular binding site as functionally relevant. Novel inhibitors with low micromolar IC50 identified by in silico screening targeting this site are active in mammalian cell water permeability assays.\",\n      \"method\": \"Homology modeling, molecular dynamics simulation, molecular docking, site-directed mutagenesis, mammalian cell water permeability assay\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus functional assay validates binding site; single lab with computational and experimental validation\",\n      \"pmids\": [\"23448163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AQP9 and monocarboxylate transporter MCT2 co-immunoprecipitate from hippocampal neuron homogenates and co-localize in mitochondria of hippocampal neurons. Glutamate exposure increases AQP9 and MCT2 protein expression post-translationally (no mRNA change), and decreases glucose utilization, suggesting AQP9 facilitates alternative fuel (monocarboxylate) access to mitochondria.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, Western blot and RT-PCR before/after glutamate treatment, glucose utilization assay in primary hippocampal neurons\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus co-localization plus functional metabolic readout; single lab\",\n      \"pmids\": [\"25161606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AQP9 is permeable to the parkinsonogenic toxin MPP+ as demonstrated by Xenopus oocyte uptake assay. Stable AQP9 expression in HEK cells increases their vulnerability to MPP+ and arsenite. AQP9 knockout in mice protects nigral dopaminergic neurons from MPP+ toxicity in organotypic midbrain slice cultures and in vivo intrastriatal injection models (48% reduction in TH+ cells in AQP9 KO vs. 67% in WT).\",\n      \"method\": \"Xenopus oocyte MPP+ uptake assay, stable HEK cell expression, cell viability, organotypic slice culture, intrastriatal MPP+ injection in AQP9 KO vs. WT mice, TH+ cell counting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal systems (oocyte, cell line, ex vivo slice, in vivo KO) with consistent results across labs\",\n      \"pmids\": [\"29566083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AQP9 acts as an astrocyte-to-neuron lactate shuttle (ANLS) in concert with monocarboxylate transporters (MCTs) to support retinal ganglion cell (RGC) function and survival. AQP9 co-localizes with MCTs 1, 2, and 4 at the ganglion cell layer and co-immunoprecipitates with these MCTs in WT retina. Aqp9-null mice show greater RGC loss and reduced electroretinographic pSTR amplitude after optic nerve crush, reduced intraretinal lactate, and elevated glucose levels; glucose transporter GLUT1 expression is compensatorily increased.\",\n      \"method\": \"Aqp9 knockout mouse with optic nerve crush model, RGC density counting, electroretinography, co-immunoprecipitation of AQP9 with MCT1/2/4, immunolabeling, intraretinal metabolite measurement, MCT2 inhibitor injection\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple functional readouts, co-IP with MCTs, and metabolic substrate quantification; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32748371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AQP9 transports lactate in macrophages: AQP9 overexpression in CHO cells increases lactate import rate; AQP9-/- macrophages and AQP9 knockdown RAW264.7 cells show reduced lactate transport. In the tumor microenvironment, AQP9-mediated lactate import drives M2-like macrophage polarization and VEGF production; AQP9-/- mice resist tumor growth and show suppressed M2 polarization in tumor tissue.\",\n      \"method\": \"AQP9 overexpression in CHO cells (lactate transport assay), AQP9-/- bone marrow-derived macrophage polarization assay, AQP9 knockdown in RAW264.7 cells, tumor allograft mouse model, VEGF ELISA\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function transport assay in CHO cells, loss-of-function in primary macrophages and cell line, and in vivo tumor model with consistent mechanistic findings\",\n      \"pmids\": [\"35967760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AQP9 in macrophages transports glycerol intracellularly where it is metabolized to lysophosphatidic acid (LPA), activating the LPAR2 receptor and downstream Hippo pathway to promote expression of cytokines IL-23 and IL-1β. AQP9 blockade in macrophages decreases inflamed macrophage cytokine expression and enhances anti-TNF therapy response in a CD mouse model.\",\n      \"method\": \"Transcriptomic analysis, AQP9-specific inhibition in macrophages, cytokine expression (ELISA, Western blot), LPA metabolite measurement, LPAR2 pathway mechanistic studies, in vivo CD mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (glycerol→LPA→LPAR2→Hippo) defined in macrophages with in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"38583685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AQP9 knockdown in PMA-stimulated neutrophils suppresses JAK2-STAT3 pathway activation, reduces pyroptosis, and decreases NET formation, thereby reducing intestinal epithelial cell injury. Reactivation of JAK2-STAT3 or pyroptosis in AQP9-knockdown neutrophils restores NET formation and epithelial damage, placing AQP9 upstream of JAK2-STAT3-mediated pyroptosis in neutrophil-driven intestinal inflammation.\",\n      \"method\": \"siRNA knockdown of AQP9 in PMA-stimulated neutrophils, Western blot for JAK2-STAT3 pathway, ELISA for cytokines, immunofluorescence for NETs, co-culture with intestinal epithelial cells, CCK-8 and TUNEL assays, DSS-induced colitis mouse model\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue with pathway agonists plus in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41504039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Selective pharmacological blockade of AQP9 (with inhibitor RG100204) significantly impairs PBMC and neutrophil migration in response to LPS. Simultaneous inhibition of both AQP3 and AQP9 is required to impair monocyte phagocytosis of K. pneumoniae (at 60 min); individual AQP9 blockade alone does not affect bacterial killing.\",\n      \"method\": \"Specific AQP9 inhibitor (HTS13286 and RG100204) treatment of human PBMCs and neutrophils, transwell migration assay with/without LPS, phagocytosis assay with K. pneumoniae, bacterial killing assay, RT-qPCR, immunofluorescence\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with specific inhibitors and defined functional readouts in primary human cells; single lab\",\n      \"pmids\": [\"40558507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"hCG treatment of normal placental explants increases AQP9 protein expression in a concentration-dependent manner via cAMP pathways (mimicked by 8-Br-cAMP), and increases water uptake 1.6-fold; AQP9 localizes to both the apical membrane and cytoplasm of syncytiotrophoblast after treatment.\",\n      \"method\": \"Placental explant culture with recombinant hCG or 8-Br-cAMP, Western blot, immunofluorescence localization, water uptake assay\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological manipulation with functional water uptake readout and localization; single lab, two orthogonal approaches\",\n      \"pmids\": [\"20220109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Insulin decreases AQP9 molecular expression in normal placental explants in a concentration-dependent manner; TNF-α pretreatment (which induces IRS phosphorylation and desensitizes insulin signaling) prevents insulin-induced AQP9 downregulation. Insulin treatment does not modify water uptake or its mercury sensitivity in placental explants, indicating AQP9 water permeability is independent of its expression level in this tissue.\",\n      \"method\": \"Placental explant culture with varying insulin concentrations, TNF-α pretreatment, Western blot for AQP9, water uptake assay with HgCl2 sensitivity\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological dissection of insulin/TNF-α regulation with multiple concentrations and functional readout; single lab\",\n      \"pmids\": [\"22018417\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AQP9 is an aquaglyceroporin channel that facilitates transmembrane flux of water, glycerol, urea, monocarboxylates (including lactate), and metalloids (arsenite, antimonite, MPP+); in hepatocytes it serves as the primary entry route for blood glycerol enabling gluconeogenesis (regulated inversely by insulin); in macrophages it imports lactate and glycerol to drive metabolic reprogramming and inflammatory cytokine production via LPA–LPAR2–Hippo signaling; in brain it localizes to the inner mitochondrial membrane of astrocytes and dopaminergic neurons where it participates in an astrocyte-to-neuron lactate shuttle (in complex with MCT1/2/4); in leukocytes it is required for cell migration and, via its metalloid permeability, determines sensitivity to arsenic-based therapeutics; and its activity can be modulated by small molecules targeting an intracellular binding site.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AQP9 is an aquaglyceroporin channel that mediates mercury-inhibitable transmembrane flux of water, urea, glycerol, monocarboxylates such as lactate, and metalloids, functioning as a multi-substrate conduit that couples solute permeability to tissue-specific metabolic and immune programs [#0, #2, #16]. Reconstitution of purified protein established robust glycerol and urea permeability, and in the liver AQP9 localizes to hepatocyte sinusoidal membranes where its expression is induced by fasting and diabetes and reversed by insulin [#2]; knockout mice exhibit elevated plasma glycerol and triglycerides with impaired fasting glucose, confirming AQP9 as the primary hepatic glycerol entry route for gluconeogenesis [#5]. Beyond water and glycerol, AQP9 transports trivalent and pentavalent arsenicals and antimonite, and this metalloid permeability makes it the uptake transporter that determines cellular sensitivity to arsenic-based chemotherapeutics [#1, #3, #9]; the same channel imports the parkinsonogenic toxin MPP+, such that AQP9 loss protects nigral dopaminergic neurons from MPP+ toxicity [#14]. In the nervous system a short mitochondrial isoform is enriched in the inner mitochondrial membrane of astrocytes and dopaminergic neurons, where AQP9 supplies glycerol and supports monocarboxylate metabolism, physically associating with monocarboxylate transporters MCT1/2/4 to operate an astrocyte-to-neuron lactate shuttle required for retinal ganglion cell survival [#4, #11, #15]. In innate immune cells AQP9 drives metabolic reprogramming and inflammation: lactate import promotes M2-like macrophage polarization and VEGF production, intracellular glycerol is converted to lysophosphatidic acid that activates LPAR2–Hippo signaling to induce IL-23 and IL-1\\u03b2, and AQP9 is required for leukocyte migration and neutrophil JAK2-STAT3-driven pyroptosis and NET formation [#16, #17, #18, #19]. AQP9 assembles as a homotetramer and possesses a functionally validated intracellular small-molecule binding site exploited for inhibitor development [#8, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the founding channel identity of AQP9 by showing it conducts water and urea but, in the initial characterization, not glycerol, placing it among the aquaporins.\",\n      \"evidence\": \"Xenopus oocyte osmotic swelling and radiolabeled solute uptake assays\",\n      \"pmids\": [\"9514918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycerol permeability not detected here, later contradicted by reconstitution\", \"No structural basis for selectivity\", \"Physiological tissue role not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed AQP9 conducts the metalloids arsenite and antimonite, revealing a toxicologically important substrate class beyond classic small solutes.\",\n      \"evidence\": \"Yeast fps1\\u0394 complementation and radiolabeled metalloid uptake in yeast and Xenopus oocytes\",\n      \"pmids\": [\"11972053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translocation mechanism for metalloids not defined\", \"In vivo relevance to arsenic handling not yet tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Reconstitution of purified protein resolved AQP9 as a high-capacity glycerol/urea channel and tied it to hepatic glycerol uptake regulated by fasting and insulin.\",\n      \"evidence\": \"Proteoliposome reconstitution, stopped-flow flux assays, hepatocyte immunolocalization, fasted/diabetic rat Western blots\",\n      \"pmids\": [\"12594337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal requirement in gluconeogenesis not yet shown by genetics\", \"Mechanism of insulin-dependent expression control unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated AQP9 is the drug-uptake transporter that confers sensitivity to arsenic trioxide chemotherapy, linking its metalloid permeability to therapeutic outcome.\",\n      \"evidence\": \"Stable AQP9 transfection in K562 cells, vitamin D induction in HL60, metalloid uptake and viability assays\",\n      \"pmids\": [\"15336539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous AQP9 regulation in patient leukemia cells not addressed\", \"Resistance mechanisms not explored\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified a short alternatively spliced AQP9 isoform enriched in the inner mitochondrial membrane of astrocytes and dopaminergic neurons, defining a distinct subcellular pool.\",\n      \"evidence\": \"Subcellular fractionation, immunogold EM, tyrosine hydroxylase double-labeling, in situ hybridization\",\n      \"pmids\": [\"16126913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; brain AQP9 expression later disputed by knockout-validated studies\", \"Transport function of the mitochondrial isoform not measured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic knockout proved AQP9 is the primary hepatic glycerol entry channel required for fasting gluconeogenesis, converting the correlative liver data into a causal role.\",\n      \"evidence\": \"AQP9 knockout mouse metabolic phenotyping, plasma glycerol/triglyceride/glucose, glycerol tolerance test, immunohistochemistry\",\n      \"pmids\": [\"17360690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain AQP9 not detected here, conflicting with the mitochondrial isoform report\", \"Compensatory glycerol routes not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected AQP9 to volume regulation and energy balance in retinal neurons, and showed insulin directly downregulates brain AQP9 in catecholaminergic neurons.\",\n      \"evidence\": \"Phloretin inhibition and volume assays in RGC-5 cells; STZ-diabetic rats and insulin-treated brainstem slice cultures\",\n      \"pmids\": [\"17337204\", \"18053968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pharmacology for the volume role\", \"Signaling link between insulin and AQP9 turnover not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined AQP9 quaternary structure as a homotetramer with knockout-validated brain expression and refined metalloid handling by distinguishing trivalent from pentavalent arsenical pathways.\",\n      \"evidence\": \"Blue native PAGE with KO controls, real-time PCR, in situ hybridization; pH-dependent arsenic uptake with Hg(II)/phloretin discrimination in oocytes\",\n      \"pmids\": [\"19115411\", \"19802720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mRNA-protein discordance in cortical neurons unexplained\", \"Atomic structure of the pore not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Loss-of-function in astrocytes confirmed AQP9 as the dominant glycerol uptake pathway whose loss forces a compensatory shift to glucose oxidation.\",\n      \"evidence\": \"AQP9 siRNA in astrocyte cultures with glycerol/glucose uptake and metabolic profiling\",\n      \"pmids\": [\"22842525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Link to neuronal fueling not tested in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Validated a functionally relevant intracellular small-molecule binding site, enabling rational AQP9 inhibitor design.\",\n      \"evidence\": \"Homology modeling, molecular dynamics/docking, site-directed mutagenesis, mammalian water permeability assays\",\n      \"pmids\": [\"23448163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of the inhibitor complex\", \"Selectivity over other aquaglyceroporins not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed AQP9 physically partners with MCT2 at neuronal mitochondria and is co-upregulated post-translationally to provide monocarboxylate fuel access.\",\n      \"evidence\": \"Co-immunoprecipitation, co-localization imaging, glutamate-treated hippocampal neuron metabolic assays\",\n      \"pmids\": [\"25161606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct AQP9 lactate transport not measured here\", \"Mechanism of post-translational co-regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established AQP9 as the conduit for MPP+ entry into dopaminergic neurons, mechanistically linking its permeability to selective neurotoxin vulnerability.\",\n      \"evidence\": \"Oocyte MPP+ uptake, HEK expression, organotypic midbrain slices, and intrastriatal MPP+ injection in AQP9 KO vs WT mice\",\n      \"pmids\": [\"29566083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to idiopathic Parkinson's disease not established\", \"Protection incomplete, implying parallel uptake routes\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated AQP9 operates within an astrocyte-to-neuron lactate shuttle in complex with MCT1/2/4 to sustain retinal ganglion cell survival under injury.\",\n      \"evidence\": \"Aqp9 KO with optic nerve crush, RGC counting, electroretinography, co-IP with MCT1/2/4, intraretinal metabolite quantification, MCT2 inhibition\",\n      \"pmids\": [\"32748371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lactate flux through AQP9 versus regulatory MCT scaffolding not separated\", \"Generalizability beyond retina untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed AQP9-mediated lactate import drives M2 macrophage polarization and VEGF production, implicating it in tumor microenvironment immunometabolism.\",\n      \"evidence\": \"CHO overexpression lactate transport, AQP9-/- and knockdown macrophage polarization, tumor allograft model, VEGF ELISA\",\n      \"pmids\": [\"35967760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from lactate to polarization not fully mapped\", \"Contribution relative to MCT lactate import not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a glycerol\\u2192LPA\\u2192LPAR2\\u2192Hippo axis through which macrophage AQP9 promotes inflammatory cytokine expression, providing a therapeutic rationale in Crohn's disease.\",\n      \"evidence\": \"Transcriptomics, AQP9 inhibition, LPA measurement, LPAR2/Hippo mechanistic studies, anti-TNF CD mouse model\",\n      \"pmids\": [\"38583685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Enzymatic steps converting glycerol to LPA not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed AQP9 upstream of neutrophil JAK2-STAT3-driven pyroptosis and NET formation and confirmed its requirement for LPS-driven leukocyte migration.\",\n      \"evidence\": \"AQP9 siRNA in PMA-stimulated neutrophils with pathway rescue, DSS colitis model; RG100204/HTS13286 inhibition with migration and phagocytosis assays in human PBMCs/neutrophils\",\n      \"pmids\": [\"41504039\", \"40558507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs; how AQP9 permeability activates JAK2-STAT3 not mechanistically resolved\", \"Phagocytosis effect requires co-inhibition with AQP3, indicating redundancy\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single channel's substrate flux is selectively decoded into divergent outcomes (gluconeogenesis, neuronal fueling, metalloid toxicity, distinct inflammatory programs) and the atomic basis of its pore and inhibitor binding remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental high-resolution structure in the corpus\", \"Tissue-specific regulation of substrate preference not mechanistically explained\", \"Direct lactate transport contribution versus MCT scaffolding not cleanly dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 14, 16]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [2, 5, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 10, 20]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 5, 11, 16]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 9, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 17, 18, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCT2\", \"MCT1\", \"MCT4\", \"CFTR\", \"LPAR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}