ArticleBlood2022
Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive normal and malignant cell growth.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Melatonin in glioblastoma therapy: clinical promise and mechanistic insights from bench to bedside.Neurosurgical review · 2026Pooled it
- Vimentin remodeling in response to oxidants and electrophiles is modulated by pH.Science advances · 2026Article
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- Intracellular pH dynamics promotes zebrafish larval tail regeneration.bioRxiv : the preprint server for biology · 2026Article
- Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility.bioRxiv : the preprint server for biology · 2026Article
- pH-regulating Lipiodol Pickering emulsions enhance transarterial embolization therapy via inducing ferroptosis and activating antitumor immunity.Cell reports. Medicine · 2026Article
- NHE1-Mediated Metabolic Reprogramming in Cancer.Metabolites · 2026Review
- Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.Nature cell biology · 2026Review
- The dysadherin/carbonic anhydrase 9 axis shapes an acidic tumor microenvironment to promote colorectal cancer progression.Signal transduction and targeted therapy · 2026Article
- Harnessing glycolysis in gastric cancer: molecular targets, therapeutic strategies, and clinical horizons.Frontiers in immunology · 2025Review
- The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities.Neoplasia (New York, N.Y.) · 2024Review
- Berberine Targets PKM2 to Activate the t-PA-Induced Fibrinolytic System and Improves Thrombosis.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Hexamethylene amiloride synergizes with venetoclax to induce lysosome-dependent cell death in acute myeloid leukemia.iScience · 2024Article
- How protons pave the way to aggressive cancers.Nature reviews. Cancer · 2023Review
- Comprehensive bioinformatics analysis of the solute carrier family and preliminary exploration of SLC25A29 in lung adenocarcinoma.Cancer cell international · 2023Article
- Article
- Proton pump inhibitors display anti-tumour potential in glioma.Cell proliferation · 2023Review
- Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer.Nature cancer · 2022Article
- Article
- Metabolic Reprogramming in Hematologic Malignancies: Advances and Clinical Perspectives.Cancer research · 2022Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Proton export is often considered a detoxifying process in animal cells, with monocarboxylate symporters coexporting excessive lactate and protons during glycolysis or the Warburg effect. We report a novel mechanism by which lactate/H+ export is sufficient to induce cell growth. Increased intracellular pH selectively activates catalysis by key metabolic gatekeeper enzymes HK1/PKM2/G6PDH, thereby enhancing glycolytic and pentose phosphate pathway carbon flux. The result is increased nucleotide levels, NADPH/NADP+ ratio, and cell proliferation. Simply increasing the lactate/proton symporter monocarboxylate transporter 4 (MCT4) or the sodium-proton antiporter NHE1 was sufficient to increase intracellular pH and give normal hematopoietic cells a significant competitive growth advantage in vivo. This process does not require additional cytokine triggers and is exploited in malignancy, where leukemogenic mutations epigenetically increase MCT4. Inhibiting MCT4 decreased intracellular pH and carbon flux and eliminated acute myeloid leukemia-initiating cells in mice without cytotoxic chemotherapy. Intracellular alkalization is a primitive mechanism by which proton partitioning can directly reprogram carbon metabolism for cell growth.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.