ArticleSignal transduction and targeted therapy2024
Malate initiates a proton-sensing pathway essential for pH regulation of inflammation.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
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- Antioxidant malic-acid-derived lipid nanoparticles delivering secretory uricase circRNA for hyperuricemia and complication management in mice.Nature communications · 2026Article
- Compression-induced metabolic adaptation drives confined tumor cell migration and distant metastasis via malate-dependent microtubule reinforcement.Cell research · 2026Article
- Liquid Biopsy in Primary CNS Tumors: Bridging Biology, Technology, and Clinical Care.Molecular diagnosis & therapy · 2026Review
- Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma.Journal of gastroenterology · 2026Article
- Conversion therapy using transarterial chemoembolization plus tislelizumab for unresectable hepatocellular carcinoma: effects on tumor necrosis and anti-tumor immune response.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Article
- mRNA vaccine development for tuberculosis: antigen design, immune mechanisms, and translational challenges.Archives of microbiology · 2026Review
- Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4.Biological trace element research · 2026Article
- Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.Molecular neurobiology · 2026Article
- Short-chain acyl-CoA dehydrogenase initiates mtDNA demethylation and leakage to fuel antitumor immunity in colorectal cancer.Signal transduction and targeted therapy · 2026Article
- Gene regulatory and biomolecular networks and their multifaceted biotechnological applications.World journal of microbiology & biotechnology · 2026Review
- Comment on "Reciprocity between p63 and p21 via TNFα/NF-κB signaling in p63-positive salivary duct adenocarcinoma cell".European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2026Article
- Combination of sodium pentaborate pentahydrate, curcumin and piperine treatment induces ferroptosis in hepatocellular carcinoma cells by regulating iron homeostasis and ROS activity in vitro.Medical oncology (Northwood, London, England) · 2026Article
- Artemisia-derived carbon dots with excellent pharmacological activities and ROS scavenging for osteoarthritis treatment.Journal of nanobiotechnology · 2026Article
- Multitarget-directed ligands in Alzheimer's disease: identification of AChE and BACE1 inhibitors by in silico approaches.Journal of computer-aided molecular design · 2025Review
- Malate targets pyruvate kinase M2 to promote colorectal cancer cell cycle arrest and tumor suppression.Molecular biomedicine · 2025Article
- Exploring the effects of ROS on PI3K/AKT/mTOR signalling in pediatric low-grade glioma and therapeutic strategies.Molecular biology reports · 2025Review
- Immunization with Complete Freund's Adjuvant Reveals Trained Immunity-like Features in A/J Mice.Vaccines · 2025Article
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Authors and funding
37 authors.
Funding
Abstract
Metabolites can double as a signaling modality that initiates physiological adaptations. Metabolism, a chemical language encoding biological information, has been recognized as a powerful principle directing inflammatory responses. Cytosolic pH is a regulator of inflammatory response in macrophages. Here, we found that L-malate exerts anti-inflammatory effect via BiP-IRF2BP2 signaling, which is a sensor of cytosolic pH in macrophages. First, L-malate, a TCA intermediate upregulated in pro-inflammatory macrophages, was identified as a potent anti-inflammatory metabolite through initial screening. Subsequent screening with DARTS and MS led to the isolation of L-malate-BiP binding. Further screening through protein‒protein interaction microarrays identified a L-malate-restrained coupling of BiP with IRF2BP2, a known anti-inflammatory protein. Interestingly, pH reduction, which promotes carboxyl protonation of L-malate, facilitates L-malate and carboxylate analogues such as succinate to bind BiP, and disrupt BiP-IRF2BP2 interaction in a carboxyl-dependent manner. Both L-malate and acidification inhibit BiP-IRF2BP2 interaction, and protect IRF2BP2 from BiP-driven degradation in macrophages. Furthermore, both in vitro and in vivo, BiP-IRF2BP2 signal is required for effects of both L-malate and pH on inflammatory responses. These findings reveal a previously unrecognized, proton/carboxylate dual sensing pathway wherein pH and L-malate regulate inflammatory responses, indicating the role of certain carboxylate metabolites as adaptors in the proton biosensing by interactions between macromolecules.
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