{"gene":"PRKAB1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2017,"finding":"Methyl-β-cyclodextrin (MβCD) directly binds to the AMPK β-subunits (PRKAB1/PRKAB2), activating AMPK and restoring impaired autophagy flux in NPC1-deficient cells; knockdown of PRKAB1 or PRKAB2 abolished MβCD-mediated reduction of cholesterol storage, identifying AMPK as the molecular target of MβCD.","method":"siRNA knockdown of PRKAB1/PRKAB2, AMPK inhibitor treatment, autophagy flux assay, cholesterol storage quantification","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss-of-function (siRNA + pharmacological inhibitor) with defined cellular phenotype in a single lab; direct binding claim based on functional evidence but no structural/biochemical binding assay described in abstract","pmids":["28613987"],"is_preprint":false},{"year":2025,"finding":"Buddleoside binds directly to the PRKAB1 subunit of AMPK via residues Val81, Arg83, and Ser108 (the ADaM site), activating AMPK, which phosphorylates RPTOR to inhibit MTORC1, thereby activating TFEB-mediated autophagy-lysosomal pathway and ameliorating NASH.","method":"CETSA (cellular thermal shift assay), DARTS (drug affinity responsive target stability assay), molecular docking, in vivo mouse NASH model, AMPK inhibition rescue experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (CETSA, DARTS) plus docking and functional rescue in single lab; no crystallographic or mutagenesis validation of binding residues in abstract","pmids":["39936600"],"is_preprint":false},{"year":2020,"finding":"PRKAB1 (AMPKβ1) is required for hematoma resolution in vivo: Prkab1-/- mice showed persistent hematomas at day 9 with increased macrophage infiltration, inflammatory activation, and oxidative stress, phenocopying ATF1-deficient mice; heme-induced HO-1 and lipid regulatory gene expression (LXR, IGF1, Spic) was lost in bone marrow-derived macrophages from Prkab1-/- mice.","method":"Prkab1 knockout mouse model, perifemoral hematoma model, bone marrow-derived macrophage assays, gene expression analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific in vivo phenotypic readout (hematoma resolution) plus in vitro mechanistic validation in macrophages; clear pathway placement (AMPK→ATF1→HO-1/lipid gene axis)","pmids":["32611235"],"is_preprint":false},{"year":2020,"finding":"Loss of PRKAB1 (AMPKβ1) in human iPSCs impairs late-stage cardiomyocyte differentiation, while loss of PRKAB2 abrogates mesoderm specification entirely, demonstrating isoform-specific roles for the two AMPKβ subunits in cardiac lineage commitment.","method":"PRKAB1 and PRKAB2 knockout in hiPSCs, RNA-Seq, cardiac marker expression (cTnT, GATA4, NKX2.5), histochemical staining","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined differentiation phenotype and multiple cardiac lineage markers; single lab, isoform-specific comparison adds orthogonal control","pmids":["33454005"],"is_preprint":false},{"year":2021,"finding":"PRKAB1 silencing inhibits flavone (apigenin/luteolin)-induced autophagic flux in HepG2 cells; furthermore, PRKAB1 (AMPKβ) functions downstream of NQO2 inhibition—NQO2 depletion increases basal AMPK phosphorylation but abrogates further AMPK activation by apigenin, placing NQO2 as a negative regulator upstream of AMPK/PRKAB1 in autophagy induction.","method":"siRNA knockdown of PRKAB1 and NQO2 in HepG2 cells, autophagic flux assay (LC3-II), AMPK phosphorylation western blot","journal":"Antioxidants (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via siRNA knockdown with defined autophagic flux readout; single lab, two orthogonal RNAi targets establishing pathway order","pmids":["34068281"],"is_preprint":false},{"year":2021,"finding":"Decreased miR-802 promotes murine Prkab1 expression (or human PRKAA1 in human cells), increasing phosphorylated AMPK levels and decreasing hepatic lipogenesis; dual-luciferase reporter assay confirmed miR-802 binds the 3'-UTR of mouse Prkab1 to suppress its expression.","method":"miRNA inhibitor/lentivirus overexpression, dual-luciferase reporter assay, pull-down, quantitative RT-PCR, western blotting","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct 3'-UTR targeting; functional rescue experiments in vivo and in vitro; single lab","pmids":["33391522"],"is_preprint":false},{"year":2024,"finding":"Schisanhenol (SAL) improves NAFLD by targeting the miR-802/AMPK pathway; liver-specific overexpression of miR-802 significantly impaired SAL-mediated liver protection and decreased phosphorylated AMPK and PRKAB1 protein levels; dual-luciferase assay confirmed miR-802 inhibits hepatic AMPK by binding the 3'-UTR of mouse Prkab1.","method":"Liver-specific miR-802 overexpression in NAFLD mice, dual-luciferase reporter assay, miRNA-seq, western blotting, genetic silencing of PRKAA1","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase 3'-UTR validation replicated from prior study; in vivo rescue experiment; single lab","pmids":["39309511"],"is_preprint":false},{"year":2023,"finding":"PRKAB1 knockout in the mCRPC cell line C4 validated by single-gene clone generation confers altered response to cabazitaxel treatment, identifying PRKAB1 as a modulator of cabazitaxel sensitivity.","method":"Genome-wide CRISPR/Cas9 knockout screen, single-gene knockout clone validation, drug response assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with validated single-gene clones and specific drug response phenotype; single lab, mechanistic pathway not detailed in abstract","pmids":["37270558"],"is_preprint":false},{"year":2025,"finding":"A clinical-grade PRKAB1 agonist reactivates CDX2-driven lineage differentiation programs, dismantles Wnt/YAP-driven stemness, and selectively eliminates CDX2-low cancer stem cells in CRC cell lines, xenografts, and patient-derived organoids, demonstrating that PRKAB1 acts as a stress polarity sensor that can be pharmacologically activated to induce differentiation therapy.","method":"CRC cell lines, xenografts, patient-derived organoids (PDOs), transcriptomic network analysis, pharmacological PRKAB1 agonism, IC50 measurements","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (cell lines, xenografts, PDOs) with specific mechanistic readout; single lab; no structural or in vitro reconstitution data described","pmids":["41118768"],"is_preprint":false},{"year":2025,"finding":"PRKAB1 is required as a stress polarity sensor for CDX2 lineage restoration in colorectal cancer; PRKAB1 agonism activates differentiation-associated stress polarity signaling while dismantling Wnt and YAP-driven stemness programs essential for cancer stem cell survival (preprint version of above peer-reviewed paper).","method":"ML-guided transcriptomic network, CRC cell lines, xenografts, PDOs, pharmacological PRKAB1 agonism","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, overlaps with peer-reviewed version; mechanistic detail limited in abstract; single lab","pmids":["37745574"],"is_preprint":true}],"current_model":"PRKAB1 encodes the β1 regulatory (non-catalytic) subunit of the heterotrimeric AMP-activated protein kinase (AMPK) complex; it serves as a scaffold and allosteric regulatory subunit that can be directly bound by small molecules (e.g., MβCD at the β-subunit, buddleoside at Val81/Arg83/Ser108 of the ADaM site) to activate AMPK, and its expression is post-transcriptionally suppressed by miR-802 via 3'-UTR binding; activated AMPK/PRKAB1 drives autophagy flux, hematoma resolution via an ATF1-HO-1/lipid gene axis in macrophages, cardiac lineage commitment in pluripotent stem cells, and differentiation of colorectal cancer stem cells by dismantling Wnt/YAP stemness programs, while its loss impairs all of these processes."},"narrative":{"mechanistic_narrative":"PRKAB1 encodes the β1 regulatory subunit of the heterotrimeric AMP-activated protein kinase (AMPK), and through its incorporation into the AMPK complex it governs autophagy, lipid metabolism, and cell-fate decisions across multiple tissues [PMID:28613987, PMID:32611235, PMID:33454005]. The β1 subunit serves as a directly druggable node: methyl-β-cyclodextrin binds the AMPK β-subunits to activate the kinase and restore autophagic flux [PMID:28613987], and buddleoside engages PRKAB1 at the ADaM site (residues Val81, Arg83, Ser108), driving AMPK-dependent RPTOR phosphorylation, MTORC1 inhibition, and TFEB-mediated activation of the autophagy-lysosomal pathway [PMID:39936600]. PRKAB1-dependent AMPK activity is required for macrophage-mediated hematoma resolution through an ATF1–HO-1/lipid-gene axis [PMID:32611235], for late-stage cardiomyocyte differentiation from iPSCs in an isoform-specific manner distinct from PRKAB2 [PMID:33454005], and for differentiation of colorectal cancer cells, where pharmacological PRKAB1 agonism reactivates CDX2-driven lineage programs and dismantles Wnt/YAP-driven stemness to eliminate cancer stem cells [PMID:41118768]. PRKAB1 expression is post-transcriptionally suppressed by miR-802 binding to its 3'-UTR, a regulatory axis controlling hepatic lipogenesis [PMID:33391522, PMID:39309511].","teleology":[{"year":2017,"claim":"Established that the AMPK β-subunits, including PRKAB1, are the direct molecular target through which a small molecule (MβCD) activates AMPK to restore autophagy, defining PRKAB1 as a druggable activation node.","evidence":"siRNA knockdown of PRKAB1/PRKAB2 plus AMPK inhibitor with autophagy flux and cholesterol storage readouts in NPC1-deficient cells","pmids":["28613987"],"confidence":"Medium","gaps":["No structural or biochemical binding assay localizing the MβCD interaction site","Does not distinguish the individual contributions of PRKAB1 versus PRKAB2"]},{"year":2020,"claim":"Demonstrated an isoform-specific developmental requirement, separating PRKAB1 (late cardiomyocyte differentiation) from PRKAB2 (mesoderm specification) in human cardiac lineage commitment.","evidence":"PRKAB1 and PRKAB2 knockout in hiPSCs with RNA-Seq and cardiac marker expression","pmids":["33454005"],"confidence":"Medium","gaps":["Downstream effectors linking PRKAB1-AMPK to cardiomyocyte maturation undefined","Single-lab study without orthogonal rescue"]},{"year":2020,"claim":"Placed PRKAB1 in an in vivo physiological pathway by showing it is required for macrophage-driven hematoma resolution via an ATF1–HO-1/lipid-gene program.","evidence":"Prkab1-/- mouse perifemoral hematoma model with bone marrow-derived macrophage assays and gene expression analysis","pmids":["32611235"],"confidence":"High","gaps":["Mechanism linking AMPKβ1 to ATF1 activation not resolved","Whether the phenotype reflects loss of catalytic AMPK activity or scaffold function untested"]},{"year":2021,"claim":"Defined upstream and downstream pathway context, placing NQO2 as a negative regulator upstream of AMPK/PRKAB1 in flavone-induced autophagy.","evidence":"siRNA knockdown of PRKAB1 and NQO2 in HepG2 cells with LC3-II flux and AMPK phosphorylation western blots","pmids":["34068281"],"confidence":"Medium","gaps":["Molecular mechanism by which NQO2 restrains AMPK unclear","Single cell line"]},{"year":2021,"claim":"Identified post-transcriptional control of PRKAB1, showing miR-802 directly binds its 3'-UTR to suppress expression and modulate hepatic lipogenesis.","evidence":"Dual-luciferase 3'-UTR reporter, miRNA inhibitor/overexpression, RT-PCR and western blot in liver models","pmids":["33391522"],"confidence":"Medium","gaps":["Human versus mouse target ambiguity (PRKAB1 vs PRKAA1)","Physiological conditions that set miR-802 levels not defined"]},{"year":2024,"claim":"Replicated and extended the miR-802/PRKAB1 axis as a therapeutic target by showing schisanhenol protects against NAFLD through this pathway.","evidence":"Liver-specific miR-802 overexpression in NAFLD mice with dual-luciferase 3'-UTR validation and western blotting","pmids":["39309511"],"confidence":"Medium","gaps":["Direct binding of schisanhenol to PRKAB1 not established","Single lab"]},{"year":2025,"claim":"Mapped a direct small-molecule binding site (ADaM site, Val81/Arg83/Ser108) on PRKAB1 and connected it to the AMPK→RPTOR→MTORC1→TFEB autophagy axis in NASH.","evidence":"CETSA, DARTS, molecular docking, and AMPK-inhibition rescue in a mouse NASH model with buddleoside","pmids":["39936600"],"confidence":"Medium","gaps":["No crystallographic or mutagenesis confirmation of the binding residues","Single-lab functional model"]},{"year":2025,"claim":"Established PRKAB1 as a pharmacologically actionable stress polarity sensor whose agonism drives CDX2 differentiation programs and eliminates Wnt/YAP-driven colorectal cancer stem cells.","evidence":"Clinical-grade PRKAB1 agonist tested in CRC cell lines, xenografts, and patient-derived organoids with transcriptomic network analysis","pmids":["41118768"],"confidence":"Medium","gaps":["Direct target engagement of the agonist on PRKAB1 not biochemically reconstituted","Mechanism linking AMPKβ1 to CDX2/Wnt/YAP not molecularly resolved"]},{"year":null,"claim":"How PRKAB1's scaffolding/regulatory role within the AMPK heterotrimer is mechanistically translated into the distinct tissue-specific outcomes (hematoma resolution, cardiac differentiation, CRC differentiation) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PRKAB1 within AMPK in the timeline","Whether phenotypes depend on catalytic AMPK output versus β1-specific scaffolding untested","Direct downstream substrates linking PRKAB1-AMPK to lineage transcription factors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8]}],"localization":[],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]}],"complexes":["AMPK heterotrimer"],"partners":["PRKAB2","RPTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y478","full_name":"5'-AMP-activated protein kinase subunit beta-1","aliases":[],"length_aa":270,"mass_kda":30.4,"function":"Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y478/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKAB1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKAA1","stoichiometry":10.0},{"gene":"MINK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRKAB1","total_profiled":1310},"omim":[{"mim_id":"610594","title":"FOLLICULIN-INTERACTING PROTEIN 1; FNIP1","url":"https://www.omim.org/entry/610594"},{"mim_id":"604976","title":"PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-3; PRKAG3","url":"https://www.omim.org/entry/604976"},{"mim_id":"602743","title":"PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-2; PRKAG2","url":"https://www.omim.org/entry/602743"},{"mim_id":"602742","title":"PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, GAMMA-1; PRKAG1","url":"https://www.omim.org/entry/602742"},{"mim_id":"602741","title":"PROTEIN KINASE, AMP-ACTIVATED, NONCATALYTIC, BETA-2; PRKAB2","url":"https://www.omim.org/entry/602741"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Primary cilium transition zone","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRKAB1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y478","domains":[{"cath_id":"2.60.40.10","chopping":"77-161","consensus_level":"high","plddt":95.8398,"start":77,"end":161},{"cath_id":"2.20.25.290","chopping":"207-268","consensus_level":"high","plddt":96.3621,"start":207,"end":268}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y478","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y478-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y478-F1-predicted_aligned_error_v6.png","plddt_mean":77.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRKAB1","jax_strain_url":"https://www.jax.org/strain/search?query=PRKAB1"},"sequence":{"accession":"Q9Y478","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y478.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y478/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y478"}},"corpus_meta":[{"pmid":"23028138","id":"PMC_23028138","title":"Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes.","date":"2012","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/23028138","citation_count":302,"is_preprint":false},{"pmid":"28613987","id":"PMC_28613987","title":"Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK.","date":"2017","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/28613987","citation_count":74,"is_preprint":false},{"pmid":"17167165","id":"PMC_17167165","title":"Adenosine 5'-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes.","date":"2006","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/17167165","citation_count":49,"is_preprint":false},{"pmid":"21324179","id":"PMC_21324179","title":"Identification of differentially expressed genes in chickens differing in muscle glycogen content and meat quality.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21324179","citation_count":39,"is_preprint":false},{"pmid":"14970694","id":"PMC_14970694","title":"Study of candidate genes for glycolytic potential of porcine skeletal muscle: identification and analysis of mutations, linkage and physical mapping and association with meat quality traits in pigs.","date":"2003","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/14970694","citation_count":36,"is_preprint":false},{"pmid":"33391522","id":"PMC_33391522","title":"Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33391522","citation_count":32,"is_preprint":false},{"pmid":"39309511","id":"PMC_39309511","title":"Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-mediated modulation of hepatic lipid metabolism.","date":"2024","source":"Acta pharmaceutica Sinica. 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knockdown of PRKAB1 or PRKAB2 abolished MβCD-mediated reduction of cholesterol storage, identifying AMPK as the molecular target of MβCD.\",\n      \"method\": \"siRNA knockdown of PRKAB1/PRKAB2, AMPK inhibitor treatment, autophagy flux assay, cholesterol storage quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss-of-function (siRNA + pharmacological inhibitor) with defined cellular phenotype in a single lab; direct binding claim based on functional evidence but no structural/biochemical binding assay described in abstract\",\n      \"pmids\": [\"28613987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Buddleoside binds directly to the PRKAB1 subunit of AMPK via residues Val81, Arg83, and Ser108 (the ADaM site), activating AMPK, which phosphorylates RPTOR to inhibit MTORC1, thereby activating TFEB-mediated autophagy-lysosomal pathway and ameliorating NASH.\",\n      \"method\": \"CETSA (cellular thermal shift assay), DARTS (drug affinity responsive target stability assay), molecular docking, in vivo mouse NASH model, AMPK inhibition rescue experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (CETSA, DARTS) plus docking and functional rescue in single lab; no crystallographic or mutagenesis validation of binding residues in abstract\",\n      \"pmids\": [\"39936600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRKAB1 (AMPKβ1) is required for hematoma resolution in vivo: Prkab1-/- mice showed persistent hematomas at day 9 with increased macrophage infiltration, inflammatory activation, and oxidative stress, phenocopying ATF1-deficient mice; heme-induced HO-1 and lipid regulatory gene expression (LXR, IGF1, Spic) was lost in bone marrow-derived macrophages from Prkab1-/- mice.\",\n      \"method\": \"Prkab1 knockout mouse model, perifemoral hematoma model, bone marrow-derived macrophage assays, gene expression analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific in vivo phenotypic readout (hematoma resolution) plus in vitro mechanistic validation in macrophages; clear pathway placement (AMPK→ATF1→HO-1/lipid gene axis)\",\n      \"pmids\": [\"32611235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of PRKAB1 (AMPKβ1) in human iPSCs impairs late-stage cardiomyocyte differentiation, while loss of PRKAB2 abrogates mesoderm specification entirely, demonstrating isoform-specific roles for the two AMPKβ subunits in cardiac lineage commitment.\",\n      \"method\": \"PRKAB1 and PRKAB2 knockout in hiPSCs, RNA-Seq, cardiac marker expression (cTnT, GATA4, NKX2.5), histochemical staining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined differentiation phenotype and multiple cardiac lineage markers; single lab, isoform-specific comparison adds orthogonal control\",\n      \"pmids\": [\"33454005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRKAB1 silencing inhibits flavone (apigenin/luteolin)-induced autophagic flux in HepG2 cells; furthermore, PRKAB1 (AMPKβ) functions downstream of NQO2 inhibition—NQO2 depletion increases basal AMPK phosphorylation but abrogates further AMPK activation by apigenin, placing NQO2 as a negative regulator upstream of AMPK/PRKAB1 in autophagy induction.\",\n      \"method\": \"siRNA knockdown of PRKAB1 and NQO2 in HepG2 cells, autophagic flux assay (LC3-II), AMPK phosphorylation western blot\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via siRNA knockdown with defined autophagic flux readout; single lab, two orthogonal RNAi targets establishing pathway order\",\n      \"pmids\": [\"34068281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Decreased miR-802 promotes murine Prkab1 expression (or human PRKAA1 in human cells), increasing phosphorylated AMPK levels and decreasing hepatic lipogenesis; dual-luciferase reporter assay confirmed miR-802 binds the 3'-UTR of mouse Prkab1 to suppress its expression.\",\n      \"method\": \"miRNA inhibitor/lentivirus overexpression, dual-luciferase reporter assay, pull-down, quantitative RT-PCR, western blotting\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct 3'-UTR targeting; functional rescue experiments in vivo and in vitro; single lab\",\n      \"pmids\": [\"33391522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Schisanhenol (SAL) improves NAFLD by targeting the miR-802/AMPK pathway; liver-specific overexpression of miR-802 significantly impaired SAL-mediated liver protection and decreased phosphorylated AMPK and PRKAB1 protein levels; dual-luciferase assay confirmed miR-802 inhibits hepatic AMPK by binding the 3'-UTR of mouse Prkab1.\",\n      \"method\": \"Liver-specific miR-802 overexpression in NAFLD mice, dual-luciferase reporter assay, miRNA-seq, western blotting, genetic silencing of PRKAA1\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase 3'-UTR validation replicated from prior study; in vivo rescue experiment; single lab\",\n      \"pmids\": [\"39309511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRKAB1 knockout in the mCRPC cell line C4 validated by single-gene clone generation confers altered response to cabazitaxel treatment, identifying PRKAB1 as a modulator of cabazitaxel sensitivity.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen, single-gene knockout clone validation, drug response assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with validated single-gene clones and specific drug response phenotype; single lab, mechanistic pathway not detailed in abstract\",\n      \"pmids\": [\"37270558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A clinical-grade PRKAB1 agonist reactivates CDX2-driven lineage differentiation programs, dismantles Wnt/YAP-driven stemness, and selectively eliminates CDX2-low cancer stem cells in CRC cell lines, xenografts, and patient-derived organoids, demonstrating that PRKAB1 acts as a stress polarity sensor that can be pharmacologically activated to induce differentiation therapy.\",\n      \"method\": \"CRC cell lines, xenografts, patient-derived organoids (PDOs), transcriptomic network analysis, pharmacological PRKAB1 agonism, IC50 measurements\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (cell lines, xenografts, PDOs) with specific mechanistic readout; single lab; no structural or in vitro reconstitution data described\",\n      \"pmids\": [\"41118768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRKAB1 is required as a stress polarity sensor for CDX2 lineage restoration in colorectal cancer; PRKAB1 agonism activates differentiation-associated stress polarity signaling while dismantling Wnt and YAP-driven stemness programs essential for cancer stem cell survival (preprint version of above peer-reviewed paper).\",\n      \"method\": \"ML-guided transcriptomic network, CRC cell lines, xenografts, PDOs, pharmacological PRKAB1 agonism\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, overlaps with peer-reviewed version; mechanistic detail limited in abstract; single lab\",\n      \"pmids\": [\"37745574\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRKAB1 encodes the β1 regulatory (non-catalytic) subunit of the heterotrimeric AMP-activated protein kinase (AMPK) complex; it serves as a scaffold and allosteric regulatory subunit that can be directly bound by small molecules (e.g., MβCD at the β-subunit, buddleoside at Val81/Arg83/Ser108 of the ADaM site) to activate AMPK, and its expression is post-transcriptionally suppressed by miR-802 via 3'-UTR binding; activated AMPK/PRKAB1 drives autophagy flux, hematoma resolution via an ATF1-HO-1/lipid gene axis in macrophages, cardiac lineage commitment in pluripotent stem cells, and differentiation of colorectal cancer stem cells by dismantling Wnt/YAP stemness programs, while its loss impairs all of these processes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKAB1 encodes the β1 regulatory subunit of the heterotrimeric AMP-activated protein kinase (AMPK), and through its incorporation into the AMPK complex it governs autophagy, lipid metabolism, and cell-fate decisions across multiple tissues [#0, #2, #3]. The β1 subunit serves as a directly druggable node: methyl-β-cyclodextrin binds the AMPK β-subunits to activate the kinase and restore autophagic flux [#0], and buddleoside engages PRKAB1 at the ADaM site (residues Val81, Arg83, Ser108), driving AMPK-dependent RPTOR phosphorylation, MTORC1 inhibition, and TFEB-mediated activation of the autophagy-lysosomal pathway [#1]. PRKAB1-dependent AMPK activity is required for macrophage-mediated hematoma resolution through an ATF1–HO-1/lipid-gene axis [#2], for late-stage cardiomyocyte differentiation from iPSCs in an isoform-specific manner distinct from PRKAB2 [#3], and for differentiation of colorectal cancer cells, where pharmacological PRKAB1 agonism reactivates CDX2-driven lineage programs and dismantles Wnt/YAP-driven stemness to eliminate cancer stem cells [#8]. PRKAB1 expression is post-transcriptionally suppressed by miR-802 binding to its 3'-UTR, a regulatory axis controlling hepatic lipogenesis [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that the AMPK β-subunits, including PRKAB1, are the direct molecular target through which a small molecule (MβCD) activates AMPK to restore autophagy, defining PRKAB1 as a druggable activation node.\",\n      \"evidence\": \"siRNA knockdown of PRKAB1/PRKAB2 plus AMPK inhibitor with autophagy flux and cholesterol storage readouts in NPC1-deficient cells\",\n      \"pmids\": [\"28613987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or biochemical binding assay localizing the MβCD interaction site\", \"Does not distinguish the individual contributions of PRKAB1 versus PRKAB2\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated an isoform-specific developmental requirement, separating PRKAB1 (late cardiomyocyte differentiation) from PRKAB2 (mesoderm specification) in human cardiac lineage commitment.\",\n      \"evidence\": \"PRKAB1 and PRKAB2 knockout in hiPSCs with RNA-Seq and cardiac marker expression\",\n      \"pmids\": [\"33454005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors linking PRKAB1-AMPK to cardiomyocyte maturation undefined\", \"Single-lab study without orthogonal rescue\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PRKAB1 in an in vivo physiological pathway by showing it is required for macrophage-driven hematoma resolution via an ATF1–HO-1/lipid-gene program.\",\n      \"evidence\": \"Prkab1-/- mouse perifemoral hematoma model with bone marrow-derived macrophage assays and gene expression analysis\",\n      \"pmids\": [\"32611235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking AMPKβ1 to ATF1 activation not resolved\", \"Whether the phenotype reflects loss of catalytic AMPK activity or scaffold function untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined upstream and downstream pathway context, placing NQO2 as a negative regulator upstream of AMPK/PRKAB1 in flavone-induced autophagy.\",\n      \"evidence\": \"siRNA knockdown of PRKAB1 and NQO2 in HepG2 cells with LC3-II flux and AMPK phosphorylation western blots\",\n      \"pmids\": [\"34068281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which NQO2 restrains AMPK unclear\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified post-transcriptional control of PRKAB1, showing miR-802 directly binds its 3'-UTR to suppress expression and modulate hepatic lipogenesis.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, miRNA inhibitor/overexpression, RT-PCR and western blot in liver models\",\n      \"pmids\": [\"33391522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human versus mouse target ambiguity (PRKAB1 vs PRKAA1)\", \"Physiological conditions that set miR-802 levels not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Replicated and extended the miR-802/PRKAB1 axis as a therapeutic target by showing schisanhenol protects against NAFLD through this pathway.\",\n      \"evidence\": \"Liver-specific miR-802 overexpression in NAFLD mice with dual-luciferase 3'-UTR validation and western blotting\",\n      \"pmids\": [\"39309511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of schisanhenol to PRKAB1 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped a direct small-molecule binding site (ADaM site, Val81/Arg83/Ser108) on PRKAB1 and connected it to the AMPK→RPTOR→MTORC1→TFEB autophagy axis in NASH.\",\n      \"evidence\": \"CETSA, DARTS, molecular docking, and AMPK-inhibition rescue in a mouse NASH model with buddleoside\",\n      \"pmids\": [\"39936600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystallographic or mutagenesis confirmation of the binding residues\", \"Single-lab functional model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established PRKAB1 as a pharmacologically actionable stress polarity sensor whose agonism drives CDX2 differentiation programs and eliminates Wnt/YAP-driven colorectal cancer stem cells.\",\n      \"evidence\": \"Clinical-grade PRKAB1 agonist tested in CRC cell lines, xenografts, and patient-derived organoids with transcriptomic network analysis\",\n      \"pmids\": [\"41118768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target engagement of the agonist on PRKAB1 not biochemically reconstituted\", \"Mechanism linking AMPKβ1 to CDX2/Wnt/YAP not molecularly resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRKAB1's scaffolding/regulatory role within the AMPK heterotrimer is mechanistically translated into the distinct tissue-specific outcomes (hematoma resolution, cardiac differentiation, CRC differentiation) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PRKAB1 within AMPK in the timeline\", \"Whether phenotypes depend on catalytic AMPK output versus β1-specific scaffolding untested\", \"Direct downstream substrates linking PRKAB1-AMPK to lineage transcription factors unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"AMPK heterotrimer\"],\n    \"partners\": [\"PRKAB2\", \"RPTOR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}