{"gene":"LDHB","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2019,"finding":"Aurora-A kinase directly interacts with and phosphorylates LDHB at serine 162, which increases LDHB activity in reducing pyruvate to lactate. Mechanistically, S162 phosphorylation relieves substrate inhibition by pyruvate, resulting in elevated conversion of pyruvate and NADH to lactate and NAD+, thereby promoting glycolytic flux and the Warburg effect. Expression of LDHB-S162A mutant blocked glycolysis and tumor growth.","method":"Co-IP, in vitro kinase assay, site-directed mutagenesis (S162A), xenograft tumor models, metabolic flux measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, multiple orthogonal methods (Co-IP, enzymatic assay, mutant rescue, in vivo model), single rigorous study","pmids":["31804482"],"is_preprint":false},{"year":2018,"finding":"SIRT5 binds LDHB and deacetylates it at lysine-329, thereby promoting LDHB enzymatic activity. Deacetylated LDHB increases autophagy and colorectal cancer cell growth. SIRT5 knockout or inhibition increased LDHB acetylation at K329 and inhibited LDHB activity, downregulating autophagy and cancer cell growth.","method":"Mass spectrometry identification of SIRT5 as binding partner, Co-IP, SIRT5 knockout/inhibition, enzymatic activity assays, in vitro and in vivo tumor growth assays","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-identified binding partner confirmed by Co-IP, enzymatic assay, KO phenotype, multiple orthogonal methods in single study","pmids":["30443978"],"is_preprint":false},{"year":2021,"finding":"R-2-hydroxyglutarate (R-2HG) suppresses aerobic glycolysis in leukemia by abrogating FTO/m6A/YTHDF2-mediated post-transcriptional upregulation of LDHB expression. Knockdown of LDHB recapitulates R-2HG-induced glycolytic inhibition, and LDHB overexpression reverses the R-2HG effect, placing LDHB downstream of the FTO/m6A axis in glycolytic regulation.","method":"shRNA knockdown, overexpression rescue experiments, m6A modification analysis, in vivo leukemogenesis model","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by knockdown and overexpression rescue, replicated in primary AML cells and in vivo, multiple orthogonal methods","pmids":["33434505"],"is_preprint":false},{"year":2024,"finding":"HMOX1 interacts with LDHB in foamy macrophages during advanced atherosclerosis. This HMOX1-LDHB interaction enables LONP1 to degrade mitochondrial transcription factor TFAM, leading to mitochondrial dysfunction and ferroptosis.","method":"Bulk and single-cell RNA sequencing, protein interaction studies, LONP1 inhibitor experiments, MitoTEMPO treatment in vivo","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and pathway placement supported by pharmacological rescue and in vivo data, single lab study","pmids":["39731912"],"is_preprint":false},{"year":2024,"finding":"LDHB inhibition in lung cancer cells decreases total intracellular glutathione (GSH) levels, specifically reducing mitochondrial GSH catabolism by gamma-L-Glutamyl transpeptidase (GGT). GSH-monoethyl ester supplementation partially rescued the reduced invasion, migration, and colony formation caused by LDHB silencing, establishing that LDHB supports metastatic potential through mitochondrial GSH catabolism.","method":"siRNA silencing, metabolic inhibitor experiments, GSH supplementation rescue, in vivo metastasis models in immunodeficient and immunocompetent mice","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic rescue experiments with metabolic inhibitors and GSH supplementation, in vivo validation, single lab","pmids":["39615645"],"is_preprint":false},{"year":2024,"finding":"LDHB interacts with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), promoting lysosomal acidification and autophagic flux. The residues leucine 57 in ATP6V1A and serine 269 in LDHB are critical for their interaction. Hydrogen sulfide (H2S) donor NaHS attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB and disrupting the LDHB-ATP6V1A interaction.","method":"RNA-Seq, Co-IP, mutagenesis of interaction residues (Leu57, Ser269), LDHB overexpression rescue, in vivo vascular remodeling model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis identifying interaction residues, in vivo validation, single lab","pmids":["39647238"],"is_preprint":false},{"year":2024,"finding":"LDHB has β cell-specific expression in human islets and limits lactate generation. LDHB inhibition amplifies LDHA-dependent lactate generation and increases basal insulin release in both mouse and human β cells. Mendelian randomization shows that low LDHB expression correlates with elevated fasting insulin.","method":"13C6 glucose labeling with GC-MS and 2D NMR metabolic mapping, LDHB inhibition in islets, Mendelian randomization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — isotope tracing with multiple spectroscopic methods, functional inhibition assays in primary human and mouse islets, Mendelian randomization","pmids":["38607916"],"is_preprint":false},{"year":2024,"finding":"STAT3 transcription factor binds the promoter region of LDHB and activates its transcription in endometrial cancer cells. LDHB in turn interacts with and upregulates MDH2 expression, promoting cancer cell malignancy.","method":"ChIP assay, dual-luciferase reporter assay, Co-IP, LDHB and STAT3 knockdown with phenotypic rescue by MDH2 overexpression","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm transcriptional regulation; Co-IP confirms LDHB-MDH2 interaction; single lab with orthogonal methods","pmids":["38381377"],"is_preprint":false},{"year":2024,"finding":"LDHB modulates lactate production and histone H3K18 lactylation at the PD-L1 promoter to promote PD-L1 expression and immune evasion in ovarian cancer. LDHB knockdown reduced H3K18 lactylation at the PD-L1 promoter and decreased PD-L1 expression, enhancing T cell killing.","method":"ChIP-qPCR, luciferase reporter assay, LDHB siRNA knockdown, T cell co-culture cytotoxicity assay, ELISA for immune factors","journal":"Cancer investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and luciferase establish epigenetic mechanism; functional T cell assay; single lab","pmids":["39587817"],"is_preprint":false},{"year":2024,"finding":"SARS-CoV-2 Spike S1 domain interacts with LDHB and inhibits its catalytic activity, leading to increased lactate levels and a metabolic switch from aerobic to anaerobic metabolism. The Spike-NAD+ interacting region mainly involves W436 within the RBD domain, suggesting Spike deprives LDHB of NAD+.","method":"AP-MS interactome, Co-IP, immunofluorescence colocalization, enzymatic activity assay in HEK-293T cells overexpressing S1","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS confirmed by Co-IP and colocalization, enzymatic inhibition demonstrated, single lab","pmids":["39147351"],"is_preprint":false},{"year":2024,"finding":"PGC-1α transcriptionally upregulates LDHB synthesis; PGC-1α overexpression increases LDHB expression, reduces protein lactylation, and induces a switch from lactate to pyruvate production in APAP-induced liver injury model.","method":"Lentiviral overexpression of SIRT1 and PGC-1α, Western blot, measurement of lactylation and mitochondrial damage markers in AML12 cells and C57/BL6 mice","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple downstream readouts including lactylation and metabolic flux, in vivo validation, single lab","pmids":["38810904"],"is_preprint":false},{"year":2024,"finding":"LDHB silencing in lung cancer cells decreases nucleotide metabolism (purine and pyrimidine biosynthesis) as shown by metabolomics of tumor xenografts, impairs DNA damage repair, and sensitizes cells to radiotherapy. Nucleotide supplementation partially rescued DNA damage caused by combined LDHB silencing and radiotherapy.","method":"Transcriptomic re-analysis, γH2AX immunofluorescence, cell cycle analysis, metabolomics of xenografts, nucleotide supplementation rescue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics plus nucleotide rescue mechanistically links LDHB to nucleotide synthesis and DNA repair; in vivo xenograft; single lab","pmids":["40158058"],"is_preprint":false},{"year":2025,"finding":"In SLE neutrophils, chronic TLR7/9 signaling represses mitochondrial LDHB expression, impairing lactate sensing and suicidal NETosis; neutrophils instead default to vital NET release. Restoring LDHB expression (via HCQ + IFNAR blockade) re-establishes suicidal NETosis and bacterial clearance.","method":"Lupus-prone mouse model, LDHB expression analysis, HCQ and anifrolumab treatment in SLE patient neutrophils, NETosis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological rescue in mouse and human cells establishes pathway placement, but preprint without full peer review","pmids":["41279671"],"is_preprint":true},{"year":2026,"finding":"LDHB deficiency in cancer-associated fibroblasts (CAFs) leads to lactate accumulation, which disrupts DUSP16-p38 interaction, causing sustained p38 activation. This reprograms CAFs into an inflammatory phenotype with CXCL8 secretion that enhances breast cancer metastasis.","method":"LDHB knockout in CAFs, Co-IP for DUSP16-p38 interaction, CXCL8 secretion assay, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes DUSP16-p38 interaction disruption mechanism, in vivo metastasis model, single lab","pmids":["41686427"],"is_preprint":false},{"year":2026,"finding":"UCHL1 deubiquitinase binds LDHB and deubiquitinates it, thereby stabilizing LDHB protein and promoting osteosarcoma progression. LDHB knockdown reversed UCHL1-driven oncogenesis.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown of UCHL1 and LDHB, xenograft model","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay confirm deubiquitination mechanism, in vivo validation, single lab","pmids":["41998400"],"is_preprint":false},{"year":2026,"finding":"LDHB K156 lactylation, regulated by the EP300/HDAC2 axis, is induced downstream of cGAS-STING-mediated glycolytic reprogramming in sepsis, amplifying NLRP3 inflammasome activation and renal injury. AAV-mediated expression of K156R lactylation-deficient LDHB reduced renal dysfunction compared to wild-type LDHB.","method":"Lactyl-proteomic screening, CLP mouse model, AAV-mediated tubule-specific expression of WT vs K156R LDHB, biochemical assays for EP300/HDAC2 regulation","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lactyl-proteomics with site-specific mutant rescue in vivo; single lab; new paper","pmids":["41796892"],"is_preprint":false},{"year":2026,"finding":"In blood-brain barrier endothelial cells, extracellular lactate upregulates LDHB, MPC1, MPC2, and PDH, driving lactate-derived pyruvate into mitochondria and fueling TCA cycle and oxidative phosphorylation. Genetic silencing of LDHB abolishes lactate-driven BEC proliferation, establishing LDHB as the entry point of an LDHB-MPC-NAD+ redox-metabolic axis.","method":"LDHB siRNA silencing, high-resolution respirometry, MPC1 inhibition, NAMPT inhibition, glucose uptake and GLUT1 measurements","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal metabolic measurements with genetic silencing in validated BBB model; single lab","pmids":["42217683"],"is_preprint":false},{"year":2025,"finding":"In Schwann cells (peripheral nerve glia), LDHB is required for motor function: SC-specific LDHB deletion caused robust motor defects, whereas motor neuron-specific deletion had little effect. In addition, Ldhb knockout mice develop progressive neuromuscular junction atrophy. Motor-neuron LDHB deficiency synergizes with ALS risk variants (TDP43-Q331K, Sod1-D83G) to produce early motor neuropathy.","method":"Cell-type-specific conditional LDHB knockout (Schwann cell vs motor neuron), neuromuscular junction histology, motor behavior assays, ALS knock-in allele genetic epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific knockouts with defined behavioral and morphological phenotypes and genetic epistasis; preprint","pmids":["bio_10.1101_2025.11.24.690227"],"is_preprint":true},{"year":2026,"finding":"YBX1 promotes LDHB expression by increasing LDHB transcriptional activity and stabilizing LDHB mRNA. Elevated LDHB drives conversion of lactate to pyruvate and then acetyl-CoA, enhancing TCA cycle activity and ATP production in intrahepatic cholangiocarcinoma cells. Lactate induces YBX1 nuclear translocation, which activates LDHB transcription in a feed-forward loop.","method":"YBX1 overexpression/knockout (CRISPR-Cas9), LDHB knockout, mRNA stability assays, metabolic flux measurements (TCA cycle activity, ATP), in vitro and in vivo tumor growth","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout with metabolic and proliferative readouts; mRNA stability assay; single lab with multiple orthogonal methods","pmids":["41577157"],"is_preprint":false},{"year":1996,"finding":"A naturally occurring LDHB variant (LDHB GUA1) carries an Arg-to-Trp substitution at residue 106 in the active site loop. This Arg106 residue is conserved across evolution and resides in the hinge of a loop that closes over the active site upon substrate binding; the substitution abolishes catalytic activity by preventing polarization of the substrate carbonyl bond, while maintaining normal kinetic properties in heterotetramers with active LDHA subunits.","method":"DNA sequencing identifying C→T transition (Arg106Trp), computer modeling using published crystal structures, kinetic analysis of heterotetramers","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural/computational modeling with natural variant; no in vitro mutagenesis performed but natural mutation provides mechanistic insight into active-site catalysis; single study","pmids":["8611651"],"is_preprint":false},{"year":2020,"finding":"LDHB interacts with CSFV non-structural protein NS3. LDHB knockdown induces mitochondrial fission and mitophagy (evidenced by decreased TOMM20 and VDAC1, and promoted ubiquitination of MFN2) and promotes NFKB signaling, creating conditions conducive to viral persistence. LDHB overexpression decreased CSFV replication.","method":"Yeast two-hybrid screening, Co-IP, GST pulldown, confocal colocalization, siRNA knockdown, dual fluorescence mitophagy reporter (mito-mRFP-EGFP), viral titer assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and GST pulldown; functional mitophagy reporter; KD and OE with viral readout; single lab","pmids":["32924761"],"is_preprint":false},{"year":2024,"finding":"FGF1/2 signaling positively regulates STAT1, which transcriptionally activates LDHA expression while suppressing LDHB expression in prostate cancer cells, thereby promoting glycolysis.","method":"RT-qPCR, Western blot, ECAR glycolysis measurements, FGF pathway inhibitor in xenograft model, STAT1 knockdown/overexpression","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STAT1 shown to suppress LDHB transcription by knockdown/overexpression with metabolic readouts; in vivo xenograft; single lab","pmids":["38764020"],"is_preprint":false},{"year":2026,"finding":"Maternal LDHB is required for NAD+/NADH redox homeostasis during the 4- to 8-cell transition in preimplantation embryo development. Inhibition of LDHB caused developmental arrest, reduced ATP, impaired mitochondrial function, and decreased NAD+/NADH ratio. Aspartate supplementation rescued developmental progression via the malate-aspartate shuttle.","method":"Transient pharmacological inhibition of LDHB in early mouse embryos, metabolic readouts (ATP, NAD+/NADH), aspartate supplementation rescue, mitochondrial function assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition in embryos with metabolic rescue by aspartate; mechanistic link to MAS; single lab, single method class","pmids":["42117986"],"is_preprint":false},{"year":2025,"finding":"LDHB silencing in pleural mesothelioma cells increases nuclear DNA damage (elevated γH2AX) by impairing nucleotide synthesis, which is reversed by nucleotide supplementation. LDHB inhibition reduced tumor growth in vivo and enhanced cisplatin efficacy.","method":"siRNA and inducible shRNA silencing, γH2AX measurement, nucleotide supplementation rescue, in vivo xenograft with cisplatin combination","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nucleotide rescue mechanistically links LDHB to DNA repair; in vivo validation; single lab","pmids":["40790017"],"is_preprint":false},{"year":2015,"finding":"LDHB promoter hypermethylation suppresses LDHB expression in pancreatic cancer, leading to glycolytic transition. Decreased LDHB expression promotes proliferation, invasion, and migration in hypoxia, establishing LDHB as a suppressor of glycolysis in this context.","method":"Promoter methylation analysis, LDHB knockdown/overexpression, functional assays (proliferation, invasion, migration), glycolysis measurements","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter methylation with functional knockdown/overexpression and metabolic readouts; single lab","pmids":["25807933"],"is_preprint":false},{"year":2022,"finding":"LDHB overexpression in CD4 T cells increases cell respiration and mitigates lactic acid-induced inhibition of intracellular cytokine production. LDHB-overexpressing T cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules.","method":"LDHB overexpression in human CD4 T cells, Seahorse metabolic assay, tumor spheroid migration assay, flow cytometry for cytokine and effector molecule expression","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with metabolic and migratory readouts in primary human T cells; single lab","pmids":["35682650"],"is_preprint":false},{"year":2025,"finding":"Mechanical stress activates IER3, which upregulates LDHB (identified as downstream target by mass spectrometry). LDHB promotes lactate production and lactylation in BMSCs, which drives osteogenic differentiation. IER3 inhibition blocked mechanical stress-induced increases in lactate and lactylation.","method":"Mass spectrometry identification of LDHB as IER3 target, uniaxial cell stretching system, IER3 knockdown with lactylation and differentiation assays","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MS identification of LDHB as IER3 downstream target confirmed by IER3 knockdown; single lab, limited mechanistic follow-up of direct LDHB regulation","pmids":["40244862"],"is_preprint":false},{"year":2025,"finding":"Visomitin directly targets STAT3, inhibiting its transcriptional activity and thereby modulating LDHB expression levels in osteoclasts, triggering metabolic reprogramming and reducing osteoclastogenesis.","method":"STAT3 targeting assay, LDHB expression analysis, osteoclastogenesis assays, in vivo bone loss model","journal":"Research (Washington, D.C.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — STAT3-LDHB axis placed by pharmacological inhibitor; limited direct mechanistic evidence for STAT3 binding to LDHB promoter; single lab","pmids":["40698330"],"is_preprint":false},{"year":2025,"finding":"Luteolin and quercetin exhibit uncompetitive inhibition of LDHB by binding at an allosteric site at the dimer interface, distinct from the active site where they competitively inhibit LDHA. This was supported by enzyme kinetic assays and molecular docking.","method":"In vitro enzyme kinetic assays (Ki determination, inhibition mode), molecular docking, virtual screening of 115 compounds","journal":"Molecules (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro kinetic assay establishes inhibition mode; docking provides structural rationale; no mutagenesis or structural validation; single lab","pmids":["40733189"],"is_preprint":false},{"year":2021,"finding":"HYOU1 promotes LDHB expression at the post-transcriptional level by stabilizing LDHB mRNA through suppression of miR-375-3p levels. LDHB overexpression rescued the inhibitory effects of HYOU1 silencing on glycolysis, proliferation, and invasion in papillary thyroid cancer cells.","method":"HYOU1 siRNA silencing, miR-375-3p measurement, 3'UTR targeting analysis, LDHB overexpression rescue of glycolysis and proliferation","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect regulation of LDHB mRNA stability via miRNA; LDHB overexpression rescue; single lab, limited direct mechanistic evidence","pmids":["33792181"],"is_preprint":false},{"year":2025,"finding":"LDHB directly interacts with PDCoV nucleocapsid (N) protein in the cytoplasm and mediates autophagic degradation of the N protein, thereby suppressing viral replication. PDCoV N protein, via its LIR motif, binds LC3 and facilitates LDHB degradation as a viral immune evasion strategy.","method":"Co-IP, yeast two-hybrid, confocal colocalization, siRNA knockdown, LDHB overexpression, viral titer assays, autophagy flux assays","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed by multiple methods; LIR motif mechanistically links N protein to LC3; functional autophagic degradation demonstrated; single lab","pmids":["40231829"],"is_preprint":false}],"current_model":"LDHB is a lactate dehydrogenase subunit that preferentially catalyzes the conversion of lactate to pyruvate (and NAD+ to NADH), supporting oxidative metabolism; its activity is regulated by multiple post-translational modifications—including Aurora-A-mediated phosphorylation at S162 (relieving substrate inhibition to increase pyruvate-to-lactate flux), SIRT5-mediated deacetylation at K329 (enhancing enzymatic activity and autophagy), and lactylation at K156 (regulated by EP300/HDAC2, linking cGAS-STING signaling to inflammasome activation)—and its expression is controlled transcriptionally by STAT3, KLF14, YBX1, and FGF-STAT1 signaling, and post-transcriptionally by the FTO/m6A/YTHDF2 axis and RNA-binding proteins; functionally, LDHB supports mitochondrial metabolism, nucleotide biosynthesis, redox (NAD+/NADH) homeostasis, and DNA damage repair, with cell-type-specific roles in β cell insulin secretion control, Schwann cell-dependent motor function, immune cell lactate tolerance, and tumor cell metabolic symbiosis."},"narrative":{"mechanistic_narrative":"LDHB is a lactate dehydrogenase subunit that interconverts lactate and pyruvate with coupled NAD+/NADH cycling, positioning it as a control point that routes carbon and redox equivalents into mitochondrial oxidative metabolism rather than fermentation [PMID:38607916, PMID:42217683]. A conserved active-site Arg106 in a substrate-closing loop is required for catalysis, and the enzyme assembles into heterotetramers with LDHA subunits [PMID:8611651]. Its directionality and activity are tuned by post-translational modifications: Aurora-A phosphorylation at S162 relieves pyruvate substrate inhibition to drive pyruvate-to-lactate flux and the Warburg effect [PMID:31804482], SIRT5-mediated deacetylation at K329 enhances activity and supports autophagy [PMID:30443978], EP300/HDAC2-regulated K156 lactylation amplifies NLRP3 inflammasome activation downstream of cGAS-STING signaling [PMID:41796892], and UCHL1-mediated deubiquitination stabilizes the protein [PMID:41998400]. LDHB controls a lactate-to-pyruvate-to-acetyl-CoA route that fuels the TCA cycle and ATP production, sustains NAD+/NADH redox homeostasis through the malate-aspartate shuttle, and supports nucleotide biosynthesis and DNA-damage repair, such that its loss impairs metastatic capacity and sensitizes tumor cells to radiotherapy and cisplatin [PMID:40158058, PMID:41577157, PMID:42117986, PMID:40790017]. By governing lactate levels, LDHB also feeds histone H3K18 lactylation at the PD-L1 promoter to promote immune evasion [PMID:39587817] and shapes cell-type-specific physiology including beta-cell insulin secretion [PMID:38607916], Schwann-cell-dependent motor function [PMID:bio_10.1101_2025.11.24.690227], and CD4 T-cell lactate tolerance [PMID:35682650]. Its expression is set by transcriptional inputs (STAT3, YBX1, PGC-1alpha, and FGF-STAT1 signaling that suppresses LDHB) and post-transcriptional control via the FTO/m6A/YTHDF2 axis and promoter methylation [PMID:33434505, PMID:38381377, PMID:38810904, PMID:41577157, PMID:38764020, PMID:25807933]. LDHB additionally serves as a host target hijacked by viral proteins from SARS-CoV-2, CSFV, and PDCoV [PMID:39147351, PMID:32924761, PMID:40231829].","teleology":[{"year":1996,"claim":"Established the catalytic basis of LDHB activity by showing a single active-site residue is essential for substrate turnover.","evidence":"Sequencing of the natural LDHB GUA1 Arg106Trp variant with crystal-structure modeling and heterotetramer kinetics","pmids":["8611651"],"confidence":"Medium","gaps":["No in vitro mutagenesis to isolate the residue's contribution","Did not address regulation of the enzyme in cells"]},{"year":2015,"claim":"Identified LDHB as a context-dependent suppressor of glycolysis whose silencing via promoter hypermethylation drives a glycolytic, pro-tumorigenic switch.","evidence":"Promoter methylation analysis with knockdown/overexpression and glycolysis assays in pancreatic cancer","pmids":["25807933"],"confidence":"Medium","gaps":["Directionality of LDHB flux not directly measured","Mechanism linking methylation to phenotype indirect"]},{"year":2018,"claim":"Revealed that LDHB activity is acetylation-regulated, connecting a sirtuin to lactate metabolism and autophagy.","evidence":"MS partner identification, Co-IP, SIRT5 KO/inhibition and enzymatic assays in colorectal cancer","pmids":["30443978"],"confidence":"High","gaps":["How K329 acetylation alters enzyme conformation unresolved","Link between activity and autophagy mechanistically incomplete"]},{"year":2019,"claim":"Showed LDHB directionality is switchable by phosphorylation, explaining how a 'lactate-to-pyruvate' enzyme can fuel the Warburg effect.","evidence":"Co-IP, in vitro Aurora-A kinase assay, S162A mutant, xenografts and flux measurements","pmids":["31804482"],"confidence":"High","gaps":["Whether S162 phosphorylation operates outside tumor contexts unknown","Structural basis for relief of substrate inhibition not solved"]},{"year":2021,"claim":"Placed LDHB downstream of an RNA-modification axis, defining a post-transcriptional layer of glycolytic control.","evidence":"shRNA, overexpression rescue and m6A analysis in AML cells and in vivo","pmids":["33434505"],"confidence":"High","gaps":["Direct YTHDF2-LDHB transcript engagement not fully mapped"]},{"year":2024,"claim":"Defined multiple transcriptional/post-transcriptional regulators (STAT3, PGC-1alpha, FGF-STAT1) and downstream effectors (MDH2, GSH catabolism), expanding LDHB's regulatory network and metabolic outputs.","evidence":"ChIP/luciferase, Co-IP, overexpression and metabolic-inhibitor rescue across endometrial, prostate, lung and liver models","pmids":["38381377","38810904","38764020","39615645"],"confidence":"Medium","gaps":["Each regulator shown in a single context","Whether these inputs converge in normal tissue unclear"]},{"year":2024,"claim":"Identified non-catalytic protein-interaction roles of LDHB in lysosomal acidification and mitochondrial TFAM degradation, broadening its function beyond enzymatic activity.","evidence":"Co-IP with interaction-residue mutagenesis (ATP6V1A L57/LDHB S269), LONP1 inhibition and in vivo vascular/atherosclerosis models","pmids":["39647238","39731912"],"confidence":"Medium","gaps":["Whether these scaffolding roles are independent of catalysis untested","Single-lab findings without reciprocal validation"]},{"year":2024,"claim":"Established LDHB as a determinant of cell-type-specific physiology and immune behavior through control of lactate levels.","evidence":"13C tracing and inhibition in human/mouse islets, ChIP-qPCR of H3K18 lactylation at PD-L1, T cell co-culture and Mendelian randomization","pmids":["38607916","39587817","35682650"],"confidence":"Medium","gaps":["Causal direction of lactylation epigenetics needs further mutant validation","Islet effect mechanism partly genetic-correlative"]},{"year":2024,"claim":"Defined LDHB as host machinery exploited or inhibited by viral proteins linking it to antiviral metabolism and autophagy.","evidence":"AP-MS/Y2H, Co-IP, mitophagy/autophagy reporters and viral titer assays for SARS-CoV-2 S1, CSFV NS3 and PDCoV N","pmids":["39147351","32924761","40231829"],"confidence":"Medium","gaps":["Physiological relevance of metabolic switch during infection unclear","Interaction interfaces only partly mapped"]},{"year":2025,"claim":"Linked LDHB-dependent nucleotide synthesis to DNA-damage repair and therapeutic sensitivity, providing a basis for combining LDHB inhibition with radio/chemotherapy.","evidence":"siRNA/shRNA silencing, gammaH2AX, metabolomics and nucleotide-supplementation rescue in lung and mesothelioma xenografts","pmids":["40158058","40790017"],"confidence":"Medium","gaps":["Step connecting LDHB metabolism to nucleotide pools indirect","Whether effect generalizes beyond these tumor types unknown"]},{"year":2025,"claim":"Demonstrated tissue-specific in vivo requirements for LDHB, including Schwann-cell-dependent motor function and immune lactate sensing.","evidence":"Cell-type-specific conditional knockouts, NMJ histology and ALS epistasis (preprint); TLR7/9-driven LDHB repression in SLE neutrophils (preprint)","pmids":["bio_10.1101_2025.11.24.690227","41279671"],"confidence":"Medium","gaps":["Preprints awaiting peer review","Molecular mechanism of LDHB in Schwann-cell support undefined"]},{"year":2026,"claim":"Resolved how LDHB protein stability and lactylation feed into inflammasome activation, redox-metabolic axes, and stromal reprogramming.","evidence":"UCHL1 deubiquitination assays, K156R lactylation-deficient mutant rescue in sepsis, YBX1 feed-forward loop, DUSP16-p38 Co-IP and LDHB-MPC-NAD+ axis in BBB endothelium","pmids":["41998400","41796892","41577157","41686427","42217683"],"confidence":"Medium","gaps":["Each mechanism shown in one disease context","Crosstalk among PTMs not integrated"]},{"year":2026,"claim":"Showed maternal LDHB is required for redox homeostasis driving early embryonic development.","evidence":"Pharmacological inhibition in mouse embryos with NAD+/NADH and ATP readouts and aspartate (malate-aspartate shuttle) rescue","pmids":["42117986"],"confidence":"Medium","gaps":["Genetic loss-of-function not performed","Specific developmental targets of redox imbalance undefined"]},{"year":null,"claim":"How the diverse post-translational modifications (phosphorylation, acetylation, lactylation, ubiquitination) are integrated to set LDHB flux directionality in any single physiological tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the modified enzyme states","No study reconciles competing context-dependent roles as glycolytic promoter vs suppressor"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6,19,28]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on 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Seriia biologicheskaia","url":"https://pubmed.ncbi.nlm.nih.gov/7804099","citation_count":2,"is_preprint":false},{"pmid":"40790017","id":"PMC_40790017","title":"Inhibition of LDHB triggers DNA damage and increases cisplatin sensitivity in pleural mesothelioma.","date":"2025","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40790017","citation_count":1,"is_preprint":false},{"pmid":"41577157","id":"PMC_41577157","title":"YBX1-LDHB axis orchestrates pyruvate production from lactate to promote ICC initiation and development.","date":"2026","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/41577157","citation_count":1,"is_preprint":false},{"pmid":"41796892","id":"PMC_41796892","title":"LDHB K156 lactylation links cGAS-STING-mediated metabolic reprogramming to NLRP3 inflammasome activation in sepsis-associated acute kidney injury.","date":"2026","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41796892","citation_count":1,"is_preprint":false},{"pmid":"39868164","id":"PMC_39868164","title":"Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39868164","citation_count":1,"is_preprint":false},{"pmid":"40231829","id":"PMC_40231829","title":"LDHB suppresses the PDCoV proliferation by targeting viral nucleocapsid protein for autophagic degradation.","date":"2025","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/40231829","citation_count":0,"is_preprint":false},{"pmid":"39459528","id":"PMC_39459528","title":"Identification of Genetic Associations of IDH2, LDHA, and LDHB Genes with Milk Yield and Compositions in Dairy Cows.","date":"2024","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39459528","citation_count":0,"is_preprint":false},{"pmid":"41686427","id":"PMC_41686427","title":"LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming That Promotes Breast Cancer Metastasis.","date":"2026","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41686427","citation_count":0,"is_preprint":false},{"pmid":"41998400","id":"PMC_41998400","title":"UCHL1 promotes osteosarcoma progression via deubiquitination and stabilization of LDHB.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41998400","citation_count":0,"is_preprint":false},{"pmid":"42065070","id":"PMC_42065070","title":"Regulation of Histone Emulsification by HPDL via LDHA/LDHB Promotes EC Cell Proliferation.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/42065070","citation_count":0,"is_preprint":false},{"pmid":"42117986","id":"PMC_42117986","title":"Maternal LDHB Safeguards Redox Balance and Developmental Competence During Preimplantation Embryo Cleavage.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/42117986","citation_count":0,"is_preprint":false},{"pmid":"41279671","id":"PMC_41279671","title":"A TLR7/9-IFNα-LDHB axis drives vital NET release and compromises antibacterial defense in lupus.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279671","citation_count":0,"is_preprint":false},{"pmid":"42217683","id":"PMC_42217683","title":"Extracellular lactate reprograms mitochondrial metabolism and NAD+/NADH redox balance in blood-brain barrier endothelial cells via an LDHB-MPC-NAD+ axis.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42217683","citation_count":0,"is_preprint":false},{"pmid":"2932822","id":"PMC_2932822","title":"Separation of the immune response genes for LDH-B and MOPC-173. III. Evidence that the failure of B10.BASR1 to respond to LDH-B is due to an antigen-presenting cell defect.","date":"1985","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/2932822","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.24.690227","title":"Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline","date":"2025-11-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.24.690227","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.19.25324051","title":"Multi-level Regulatory Roles of Lactate Metabolism Gene Network in Oral Cancer: Machine Learning Insights","date":"2025-03-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.19.25324051","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39277,"output_tokens":7744,"usd":0.116996,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17308,"output_tokens":4249,"usd":0.096382,"stage2_stop_reason":"end_turn"},"total_usd":0.213378,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Aurora-A kinase directly interacts with and phosphorylates LDHB at serine 162, which increases LDHB activity in reducing pyruvate to lactate. Mechanistically, S162 phosphorylation relieves substrate inhibition by pyruvate, resulting in elevated conversion of pyruvate and NADH to lactate and NAD+, thereby promoting glycolytic flux and the Warburg effect. Expression of LDHB-S162A mutant blocked glycolysis and tumor growth.\",\n      \"method\": \"Co-IP, in vitro kinase assay, site-directed mutagenesis (S162A), xenograft tumor models, metabolic flux measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, multiple orthogonal methods (Co-IP, enzymatic assay, mutant rescue, in vivo model), single rigorous study\",\n      \"pmids\": [\"31804482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SIRT5 binds LDHB and deacetylates it at lysine-329, thereby promoting LDHB enzymatic activity. Deacetylated LDHB increases autophagy and colorectal cancer cell growth. SIRT5 knockout or inhibition increased LDHB acetylation at K329 and inhibited LDHB activity, downregulating autophagy and cancer cell growth.\",\n      \"method\": \"Mass spectrometry identification of SIRT5 as binding partner, Co-IP, SIRT5 knockout/inhibition, enzymatic activity assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified binding partner confirmed by Co-IP, enzymatic assay, KO phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30443978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"R-2-hydroxyglutarate (R-2HG) suppresses aerobic glycolysis in leukemia by abrogating FTO/m6A/YTHDF2-mediated post-transcriptional upregulation of LDHB expression. Knockdown of LDHB recapitulates R-2HG-induced glycolytic inhibition, and LDHB overexpression reverses the R-2HG effect, placing LDHB downstream of the FTO/m6A axis in glycolytic regulation.\",\n      \"method\": \"shRNA knockdown, overexpression rescue experiments, m6A modification analysis, in vivo leukemogenesis model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by knockdown and overexpression rescue, replicated in primary AML cells and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"33434505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMOX1 interacts with LDHB in foamy macrophages during advanced atherosclerosis. This HMOX1-LDHB interaction enables LONP1 to degrade mitochondrial transcription factor TFAM, leading to mitochondrial dysfunction and ferroptosis.\",\n      \"method\": \"Bulk and single-cell RNA sequencing, protein interaction studies, LONP1 inhibitor experiments, MitoTEMPO treatment in vivo\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and pathway placement supported by pharmacological rescue and in vivo data, single lab study\",\n      \"pmids\": [\"39731912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LDHB inhibition in lung cancer cells decreases total intracellular glutathione (GSH) levels, specifically reducing mitochondrial GSH catabolism by gamma-L-Glutamyl transpeptidase (GGT). GSH-monoethyl ester supplementation partially rescued the reduced invasion, migration, and colony formation caused by LDHB silencing, establishing that LDHB supports metastatic potential through mitochondrial GSH catabolism.\",\n      \"method\": \"siRNA silencing, metabolic inhibitor experiments, GSH supplementation rescue, in vivo metastasis models in immunodeficient and immunocompetent mice\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic rescue experiments with metabolic inhibitors and GSH supplementation, in vivo validation, single lab\",\n      \"pmids\": [\"39615645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LDHB interacts with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), promoting lysosomal acidification and autophagic flux. The residues leucine 57 in ATP6V1A and serine 269 in LDHB are critical for their interaction. Hydrogen sulfide (H2S) donor NaHS attenuates disturbed flow-induced vascular remodeling by inhibiting LDHB and disrupting the LDHB-ATP6V1A interaction.\",\n      \"method\": \"RNA-Seq, Co-IP, mutagenesis of interaction residues (Leu57, Ser269), LDHB overexpression rescue, in vivo vascular remodeling model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis identifying interaction residues, in vivo validation, single lab\",\n      \"pmids\": [\"39647238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LDHB has β cell-specific expression in human islets and limits lactate generation. LDHB inhibition amplifies LDHA-dependent lactate generation and increases basal insulin release in both mouse and human β cells. Mendelian randomization shows that low LDHB expression correlates with elevated fasting insulin.\",\n      \"method\": \"13C6 glucose labeling with GC-MS and 2D NMR metabolic mapping, LDHB inhibition in islets, Mendelian randomization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — isotope tracing with multiple spectroscopic methods, functional inhibition assays in primary human and mouse islets, Mendelian randomization\",\n      \"pmids\": [\"38607916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAT3 transcription factor binds the promoter region of LDHB and activates its transcription in endometrial cancer cells. LDHB in turn interacts with and upregulates MDH2 expression, promoting cancer cell malignancy.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, Co-IP, LDHB and STAT3 knockdown with phenotypic rescue by MDH2 overexpression\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm transcriptional regulation; Co-IP confirms LDHB-MDH2 interaction; single lab with orthogonal methods\",\n      \"pmids\": [\"38381377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LDHB modulates lactate production and histone H3K18 lactylation at the PD-L1 promoter to promote PD-L1 expression and immune evasion in ovarian cancer. LDHB knockdown reduced H3K18 lactylation at the PD-L1 promoter and decreased PD-L1 expression, enhancing T cell killing.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, LDHB siRNA knockdown, T cell co-culture cytotoxicity assay, ELISA for immune factors\",\n      \"journal\": \"Cancer investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and luciferase establish epigenetic mechanism; functional T cell assay; single lab\",\n      \"pmids\": [\"39587817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SARS-CoV-2 Spike S1 domain interacts with LDHB and inhibits its catalytic activity, leading to increased lactate levels and a metabolic switch from aerobic to anaerobic metabolism. The Spike-NAD+ interacting region mainly involves W436 within the RBD domain, suggesting Spike deprives LDHB of NAD+.\",\n      \"method\": \"AP-MS interactome, Co-IP, immunofluorescence colocalization, enzymatic activity assay in HEK-293T cells overexpressing S1\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS confirmed by Co-IP and colocalization, enzymatic inhibition demonstrated, single lab\",\n      \"pmids\": [\"39147351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PGC-1α transcriptionally upregulates LDHB synthesis; PGC-1α overexpression increases LDHB expression, reduces protein lactylation, and induces a switch from lactate to pyruvate production in APAP-induced liver injury model.\",\n      \"method\": \"Lentiviral overexpression of SIRT1 and PGC-1α, Western blot, measurement of lactylation and mitochondrial damage markers in AML12 cells and C57/BL6 mice\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple downstream readouts including lactylation and metabolic flux, in vivo validation, single lab\",\n      \"pmids\": [\"38810904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LDHB silencing in lung cancer cells decreases nucleotide metabolism (purine and pyrimidine biosynthesis) as shown by metabolomics of tumor xenografts, impairs DNA damage repair, and sensitizes cells to radiotherapy. Nucleotide supplementation partially rescued DNA damage caused by combined LDHB silencing and radiotherapy.\",\n      \"method\": \"Transcriptomic re-analysis, γH2AX immunofluorescence, cell cycle analysis, metabolomics of xenografts, nucleotide supplementation rescue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics plus nucleotide rescue mechanistically links LDHB to nucleotide synthesis and DNA repair; in vivo xenograft; single lab\",\n      \"pmids\": [\"40158058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In SLE neutrophils, chronic TLR7/9 signaling represses mitochondrial LDHB expression, impairing lactate sensing and suicidal NETosis; neutrophils instead default to vital NET release. Restoring LDHB expression (via HCQ + IFNAR blockade) re-establishes suicidal NETosis and bacterial clearance.\",\n      \"method\": \"Lupus-prone mouse model, LDHB expression analysis, HCQ and anifrolumab treatment in SLE patient neutrophils, NETosis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological rescue in mouse and human cells establishes pathway placement, but preprint without full peer review\",\n      \"pmids\": [\"41279671\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LDHB deficiency in cancer-associated fibroblasts (CAFs) leads to lactate accumulation, which disrupts DUSP16-p38 interaction, causing sustained p38 activation. This reprograms CAFs into an inflammatory phenotype with CXCL8 secretion that enhances breast cancer metastasis.\",\n      \"method\": \"LDHB knockout in CAFs, Co-IP for DUSP16-p38 interaction, CXCL8 secretion assay, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes DUSP16-p38 interaction disruption mechanism, in vivo metastasis model, single lab\",\n      \"pmids\": [\"41686427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"UCHL1 deubiquitinase binds LDHB and deubiquitinates it, thereby stabilizing LDHB protein and promoting osteosarcoma progression. LDHB knockdown reversed UCHL1-driven oncogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown of UCHL1 and LDHB, xenograft model\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay confirm deubiquitination mechanism, in vivo validation, single lab\",\n      \"pmids\": [\"41998400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LDHB K156 lactylation, regulated by the EP300/HDAC2 axis, is induced downstream of cGAS-STING-mediated glycolytic reprogramming in sepsis, amplifying NLRP3 inflammasome activation and renal injury. AAV-mediated expression of K156R lactylation-deficient LDHB reduced renal dysfunction compared to wild-type LDHB.\",\n      \"method\": \"Lactyl-proteomic screening, CLP mouse model, AAV-mediated tubule-specific expression of WT vs K156R LDHB, biochemical assays for EP300/HDAC2 regulation\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lactyl-proteomics with site-specific mutant rescue in vivo; single lab; new paper\",\n      \"pmids\": [\"41796892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In blood-brain barrier endothelial cells, extracellular lactate upregulates LDHB, MPC1, MPC2, and PDH, driving lactate-derived pyruvate into mitochondria and fueling TCA cycle and oxidative phosphorylation. Genetic silencing of LDHB abolishes lactate-driven BEC proliferation, establishing LDHB as the entry point of an LDHB-MPC-NAD+ redox-metabolic axis.\",\n      \"method\": \"LDHB siRNA silencing, high-resolution respirometry, MPC1 inhibition, NAMPT inhibition, glucose uptake and GLUT1 measurements\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal metabolic measurements with genetic silencing in validated BBB model; single lab\",\n      \"pmids\": [\"42217683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Schwann cells (peripheral nerve glia), LDHB is required for motor function: SC-specific LDHB deletion caused robust motor defects, whereas motor neuron-specific deletion had little effect. In addition, Ldhb knockout mice develop progressive neuromuscular junction atrophy. Motor-neuron LDHB deficiency synergizes with ALS risk variants (TDP43-Q331K, Sod1-D83G) to produce early motor neuropathy.\",\n      \"method\": \"Cell-type-specific conditional LDHB knockout (Schwann cell vs motor neuron), neuromuscular junction histology, motor behavior assays, ALS knock-in allele genetic epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific knockouts with defined behavioral and morphological phenotypes and genetic epistasis; preprint\",\n      \"pmids\": [\"bio_10.1101_2025.11.24.690227\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YBX1 promotes LDHB expression by increasing LDHB transcriptional activity and stabilizing LDHB mRNA. Elevated LDHB drives conversion of lactate to pyruvate and then acetyl-CoA, enhancing TCA cycle activity and ATP production in intrahepatic cholangiocarcinoma cells. Lactate induces YBX1 nuclear translocation, which activates LDHB transcription in a feed-forward loop.\",\n      \"method\": \"YBX1 overexpression/knockout (CRISPR-Cas9), LDHB knockout, mRNA stability assays, metabolic flux measurements (TCA cycle activity, ATP), in vitro and in vivo tumor growth\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout with metabolic and proliferative readouts; mRNA stability assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41577157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A naturally occurring LDHB variant (LDHB GUA1) carries an Arg-to-Trp substitution at residue 106 in the active site loop. This Arg106 residue is conserved across evolution and resides in the hinge of a loop that closes over the active site upon substrate binding; the substitution abolishes catalytic activity by preventing polarization of the substrate carbonyl bond, while maintaining normal kinetic properties in heterotetramers with active LDHA subunits.\",\n      \"method\": \"DNA sequencing identifying C→T transition (Arg106Trp), computer modeling using published crystal structures, kinetic analysis of heterotetramers\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural/computational modeling with natural variant; no in vitro mutagenesis performed but natural mutation provides mechanistic insight into active-site catalysis; single study\",\n      \"pmids\": [\"8611651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LDHB interacts with CSFV non-structural protein NS3. LDHB knockdown induces mitochondrial fission and mitophagy (evidenced by decreased TOMM20 and VDAC1, and promoted ubiquitination of MFN2) and promotes NFKB signaling, creating conditions conducive to viral persistence. LDHB overexpression decreased CSFV replication.\",\n      \"method\": \"Yeast two-hybrid screening, Co-IP, GST pulldown, confocal colocalization, siRNA knockdown, dual fluorescence mitophagy reporter (mito-mRFP-EGFP), viral titer assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and GST pulldown; functional mitophagy reporter; KD and OE with viral readout; single lab\",\n      \"pmids\": [\"32924761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGF1/2 signaling positively regulates STAT1, which transcriptionally activates LDHA expression while suppressing LDHB expression in prostate cancer cells, thereby promoting glycolysis.\",\n      \"method\": \"RT-qPCR, Western blot, ECAR glycolysis measurements, FGF pathway inhibitor in xenograft model, STAT1 knockdown/overexpression\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STAT1 shown to suppress LDHB transcription by knockdown/overexpression with metabolic readouts; in vivo xenograft; single lab\",\n      \"pmids\": [\"38764020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Maternal LDHB is required for NAD+/NADH redox homeostasis during the 4- to 8-cell transition in preimplantation embryo development. Inhibition of LDHB caused developmental arrest, reduced ATP, impaired mitochondrial function, and decreased NAD+/NADH ratio. Aspartate supplementation rescued developmental progression via the malate-aspartate shuttle.\",\n      \"method\": \"Transient pharmacological inhibition of LDHB in early mouse embryos, metabolic readouts (ATP, NAD+/NADH), aspartate supplementation rescue, mitochondrial function assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition in embryos with metabolic rescue by aspartate; mechanistic link to MAS; single lab, single method class\",\n      \"pmids\": [\"42117986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LDHB silencing in pleural mesothelioma cells increases nuclear DNA damage (elevated γH2AX) by impairing nucleotide synthesis, which is reversed by nucleotide supplementation. LDHB inhibition reduced tumor growth in vivo and enhanced cisplatin efficacy.\",\n      \"method\": \"siRNA and inducible shRNA silencing, γH2AX measurement, nucleotide supplementation rescue, in vivo xenograft with cisplatin combination\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nucleotide rescue mechanistically links LDHB to DNA repair; in vivo validation; single lab\",\n      \"pmids\": [\"40790017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LDHB promoter hypermethylation suppresses LDHB expression in pancreatic cancer, leading to glycolytic transition. Decreased LDHB expression promotes proliferation, invasion, and migration in hypoxia, establishing LDHB as a suppressor of glycolysis in this context.\",\n      \"method\": \"Promoter methylation analysis, LDHB knockdown/overexpression, functional assays (proliferation, invasion, migration), glycolysis measurements\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter methylation with functional knockdown/overexpression and metabolic readouts; single lab\",\n      \"pmids\": [\"25807933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LDHB overexpression in CD4 T cells increases cell respiration and mitigates lactic acid-induced inhibition of intracellular cytokine production. LDHB-overexpressing T cells preferentially migrated into HCT116 tumor spheroids and displayed higher expression of cytotoxic effector molecules.\",\n      \"method\": \"LDHB overexpression in human CD4 T cells, Seahorse metabolic assay, tumor spheroid migration assay, flow cytometry for cytokine and effector molecule expression\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with metabolic and migratory readouts in primary human T cells; single lab\",\n      \"pmids\": [\"35682650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mechanical stress activates IER3, which upregulates LDHB (identified as downstream target by mass spectrometry). LDHB promotes lactate production and lactylation in BMSCs, which drives osteogenic differentiation. IER3 inhibition blocked mechanical stress-induced increases in lactate and lactylation.\",\n      \"method\": \"Mass spectrometry identification of LDHB as IER3 target, uniaxial cell stretching system, IER3 knockdown with lactylation and differentiation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MS identification of LDHB as IER3 downstream target confirmed by IER3 knockdown; single lab, limited mechanistic follow-up of direct LDHB regulation\",\n      \"pmids\": [\"40244862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Visomitin directly targets STAT3, inhibiting its transcriptional activity and thereby modulating LDHB expression levels in osteoclasts, triggering metabolic reprogramming and reducing osteoclastogenesis.\",\n      \"method\": \"STAT3 targeting assay, LDHB expression analysis, osteoclastogenesis assays, in vivo bone loss model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — STAT3-LDHB axis placed by pharmacological inhibitor; limited direct mechanistic evidence for STAT3 binding to LDHB promoter; single lab\",\n      \"pmids\": [\"40698330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Luteolin and quercetin exhibit uncompetitive inhibition of LDHB by binding at an allosteric site at the dimer interface, distinct from the active site where they competitively inhibit LDHA. This was supported by enzyme kinetic assays and molecular docking.\",\n      \"method\": \"In vitro enzyme kinetic assays (Ki determination, inhibition mode), molecular docking, virtual screening of 115 compounds\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinetic assay establishes inhibition mode; docking provides structural rationale; no mutagenesis or structural validation; single lab\",\n      \"pmids\": [\"40733189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HYOU1 promotes LDHB expression at the post-transcriptional level by stabilizing LDHB mRNA through suppression of miR-375-3p levels. LDHB overexpression rescued the inhibitory effects of HYOU1 silencing on glycolysis, proliferation, and invasion in papillary thyroid cancer cells.\",\n      \"method\": \"HYOU1 siRNA silencing, miR-375-3p measurement, 3'UTR targeting analysis, LDHB overexpression rescue of glycolysis and proliferation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect regulation of LDHB mRNA stability via miRNA; LDHB overexpression rescue; single lab, limited direct mechanistic evidence\",\n      \"pmids\": [\"33792181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LDHB directly interacts with PDCoV nucleocapsid (N) protein in the cytoplasm and mediates autophagic degradation of the N protein, thereby suppressing viral replication. PDCoV N protein, via its LIR motif, binds LC3 and facilitates LDHB degradation as a viral immune evasion strategy.\",\n      \"method\": \"Co-IP, yeast two-hybrid, confocal colocalization, siRNA knockdown, LDHB overexpression, viral titer assays, autophagy flux assays\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed by multiple methods; LIR motif mechanistically links N protein to LC3; functional autophagic degradation demonstrated; single lab\",\n      \"pmids\": [\"40231829\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LDHB is a lactate dehydrogenase subunit that preferentially catalyzes the conversion of lactate to pyruvate (and NAD+ to NADH), supporting oxidative metabolism; its activity is regulated by multiple post-translational modifications—including Aurora-A-mediated phosphorylation at S162 (relieving substrate inhibition to increase pyruvate-to-lactate flux), SIRT5-mediated deacetylation at K329 (enhancing enzymatic activity and autophagy), and lactylation at K156 (regulated by EP300/HDAC2, linking cGAS-STING signaling to inflammasome activation)—and its expression is controlled transcriptionally by STAT3, KLF14, YBX1, and FGF-STAT1 signaling, and post-transcriptionally by the FTO/m6A/YTHDF2 axis and RNA-binding proteins; functionally, LDHB supports mitochondrial metabolism, nucleotide biosynthesis, redox (NAD+/NADH) homeostasis, and DNA damage repair, with cell-type-specific roles in β cell insulin secretion control, Schwann cell-dependent motor function, immune cell lactate tolerance, and tumor cell metabolic symbiosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LDHB is a lactate dehydrogenase subunit that interconverts lactate and pyruvate with coupled NAD+/NADH cycling, positioning it as a control point that routes carbon and redox equivalents into mitochondrial oxidative metabolism rather than fermentation [#6, #16]. A conserved active-site Arg106 in a substrate-closing loop is required for catalysis, and the enzyme assembles into heterotetramers with LDHA subunits [#19]. Its directionality and activity are tuned by post-translational modifications: Aurora-A phosphorylation at S162 relieves pyruvate substrate inhibition to drive pyruvate-to-lactate flux and the Warburg effect [#0], SIRT5-mediated deacetylation at K329 enhances activity and supports autophagy [#1], EP300/HDAC2-regulated K156 lactylation amplifies NLRP3 inflammasome activation downstream of cGAS-STING signaling [#15], and UCHL1-mediated deubiquitination stabilizes the protein [#14]. LDHB controls a lactate-to-pyruvate-to-acetyl-CoA route that fuels the TCA cycle and ATP production, sustains NAD+/NADH redox homeostasis through the malate-aspartate shuttle, and supports nucleotide biosynthesis and DNA-damage repair, such that its loss impairs metastatic capacity and sensitizes tumor cells to radiotherapy and cisplatin [#11, #18, #22, #23]. By governing lactate levels, LDHB also feeds histone H3K18 lactylation at the PD-L1 promoter to promote immune evasion [#8] and shapes cell-type-specific physiology including beta-cell insulin secretion [#6], Schwann-cell-dependent motor function [#17], and CD4 T-cell lactate tolerance [#25]. Its expression is set by transcriptional inputs (STAT3, YBX1, PGC-1alpha, and FGF-STAT1 signaling that suppresses LDHB) and post-transcriptional control via the FTO/m6A/YTHDF2 axis and promoter methylation [#2, #7, #10, #18, #21, #24]. LDHB additionally serves as a host target hijacked by viral proteins from SARS-CoV-2, CSFV, and PDCoV [#9, #20, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the catalytic basis of LDHB activity by showing a single active-site residue is essential for substrate turnover.\",\n      \"evidence\": \"Sequencing of the natural LDHB GUA1 Arg106Trp variant with crystal-structure modeling and heterotetramer kinetics\",\n      \"pmids\": [\"8611651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro mutagenesis to isolate the residue's contribution\", \"Did not address regulation of the enzyme in cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified LDHB as a context-dependent suppressor of glycolysis whose silencing via promoter hypermethylation drives a glycolytic, pro-tumorigenic switch.\",\n      \"evidence\": \"Promoter methylation analysis with knockdown/overexpression and glycolysis assays in pancreatic cancer\",\n      \"pmids\": [\"25807933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of LDHB flux not directly measured\", \"Mechanism linking methylation to phenotype indirect\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that LDHB activity is acetylation-regulated, connecting a sirtuin to lactate metabolism and autophagy.\",\n      \"evidence\": \"MS partner identification, Co-IP, SIRT5 KO/inhibition and enzymatic assays in colorectal cancer\",\n      \"pmids\": [\"30443978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How K329 acetylation alters enzyme conformation unresolved\", \"Link between activity and autophagy mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LDHB directionality is switchable by phosphorylation, explaining how a 'lactate-to-pyruvate' enzyme can fuel the Warburg effect.\",\n      \"evidence\": \"Co-IP, in vitro Aurora-A kinase assay, S162A mutant, xenografts and flux measurements\",\n      \"pmids\": [\"31804482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S162 phosphorylation operates outside tumor contexts unknown\", \"Structural basis for relief of substrate inhibition not solved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed LDHB downstream of an RNA-modification axis, defining a post-transcriptional layer of glycolytic control.\",\n      \"evidence\": \"shRNA, overexpression rescue and m6A analysis in AML cells and in vivo\",\n      \"pmids\": [\"33434505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YTHDF2-LDHB transcript engagement not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined multiple transcriptional/post-transcriptional regulators (STAT3, PGC-1alpha, FGF-STAT1) and downstream effectors (MDH2, GSH catabolism), expanding LDHB's regulatory network and metabolic outputs.\",\n      \"evidence\": \"ChIP/luciferase, Co-IP, overexpression and metabolic-inhibitor rescue across endometrial, prostate, lung and liver models\",\n      \"pmids\": [\"38381377\", \"38810904\", \"38764020\", \"39615645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each regulator shown in a single context\", \"Whether these inputs converge in normal tissue unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified non-catalytic protein-interaction roles of LDHB in lysosomal acidification and mitochondrial TFAM degradation, broadening its function beyond enzymatic activity.\",\n      \"evidence\": \"Co-IP with interaction-residue mutagenesis (ATP6V1A L57/LDHB S269), LONP1 inhibition and in vivo vascular/atherosclerosis models\",\n      \"pmids\": [\"39647238\", \"39731912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these scaffolding roles are independent of catalysis untested\", \"Single-lab findings without reciprocal validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established LDHB as a determinant of cell-type-specific physiology and immune behavior through control of lactate levels.\",\n      \"evidence\": \"13C tracing and inhibition in human/mouse islets, ChIP-qPCR of H3K18 lactylation at PD-L1, T cell co-culture and Mendelian randomization\",\n      \"pmids\": [\"38607916\", \"39587817\", \"35682650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction of lactylation epigenetics needs further mutant validation\", \"Islet effect mechanism partly genetic-correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined LDHB as host machinery exploited or inhibited by viral proteins linking it to antiviral metabolism and autophagy.\",\n      \"evidence\": \"AP-MS/Y2H, Co-IP, mitophagy/autophagy reporters and viral titer assays for SARS-CoV-2 S1, CSFV NS3 and PDCoV N\",\n      \"pmids\": [\"39147351\", \"32924761\", \"40231829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of metabolic switch during infection unclear\", \"Interaction interfaces only partly mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked LDHB-dependent nucleotide synthesis to DNA-damage repair and therapeutic sensitivity, providing a basis for combining LDHB inhibition with radio/chemotherapy.\",\n      \"evidence\": \"siRNA/shRNA silencing, gammaH2AX, metabolomics and nucleotide-supplementation rescue in lung and mesothelioma xenografts\",\n      \"pmids\": [\"40158058\", \"40790017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step connecting LDHB metabolism to nucleotide pools indirect\", \"Whether effect generalizes beyond these tumor types unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated tissue-specific in vivo requirements for LDHB, including Schwann-cell-dependent motor function and immune lactate sensing.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts, NMJ histology and ALS epistasis (preprint); TLR7/9-driven LDHB repression in SLE neutrophils (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.24.690227\", \"41279671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprints awaiting peer review\", \"Molecular mechanism of LDHB in Schwann-cell support undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved how LDHB protein stability and lactylation feed into inflammasome activation, redox-metabolic axes, and stromal reprogramming.\",\n      \"evidence\": \"UCHL1 deubiquitination assays, K156R lactylation-deficient mutant rescue in sepsis, YBX1 feed-forward loop, DUSP16-p38 Co-IP and LDHB-MPC-NAD+ axis in BBB endothelium\",\n      \"pmids\": [\"41998400\", \"41796892\", \"41577157\", \"41686427\", \"42217683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each mechanism shown in one disease context\", \"Crosstalk among PTMs not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed maternal LDHB is required for redox homeostasis driving early embryonic development.\",\n      \"evidence\": \"Pharmacological inhibition in mouse embryos with NAD+/NADH and ATP readouts and aspartate (malate-aspartate shuttle) rescue\",\n      \"pmids\": [\"42117986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic loss-of-function not performed\", \"Specific developmental targets of redox imbalance undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse post-translational modifications (phosphorylation, acetylation, lactylation, ubiquitination) are integrated to set LDHB flux directionality in any single physiological tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the modified enzyme states\", \"No study reconciles competing context-dependent roles as glycolytic promoter vs suppressor\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6, 19, 28]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 6, 16, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 4, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6, 16, 18, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 18, 29]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 5, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LDHA\", \"SIRT5\", \"AURKA\", \"ATP6V1A\", \"MDH2\", \"UCHL1\", \"HMOX1\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}