ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate-Induced Collagen Synthesis in Fibroblasts Via the TGF-β Signaling.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- Lactylation: Metabolic epigenetic regulation and cell death mechanisms in myocardial ischemia‒reperfusion injury.Genes & diseases · 2027Review
- The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026Review
- KAT8-mediated epigenetic modifications: Physiological functions, heterogeneity in disease, and advances in targeted development.iScience · 2026Review
- Targeting the immune-metabolic axis reverses orthodontics-induced systemic pathology.Signal transduction and targeted therapy · 2026Article
- Article
- Lactylation-driven therapeutic resistance in cancer: Mechanisms and therapeutic opportunities.Genes & diseases · 2026Review
- Advances in skin aging: integrating epigenetic, cellular, and immune mechanisms for targeted therapy.Immunity & ageing : I & A · 2026Review
- Lactylation modification in extracellular vesicles: A key regulator of cellular communication.iScience · 2026Review
- Role of LDHA in senescent fibroblast exosomes promoting ferroptosis via histone lactylation-mediated ACSL4 regulation in skin photoaging.Epigenetics & chromatin · 2026Article
- Lactylation enzymes in cancer: Mechanisms and novel therapeutic approaches (Review).Oncology letters · 2026Review
- Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances.Signal transduction and targeted therapy · 2026Review
- Lactylation-regulated ferroptosis: mechanisms, disease associations, and therapeutic strategies.Archives of pharmacal research · 2026Review
- Mossy-textured hydroxyapatite-modified poly (lactic-co-glycolic acid) microspheres promote collagen regeneration via calcium/TGF-β and chemokine signaling pathways in soft tissue augmentation.Bioactive materials · 2026Article
- MicroRNA-493-5p engineered exosomes delivered via piezoelectric microneedles for epigenetic modulation of macrophages in diabetic wound healing.Materials today. Bio · 2026Article
- SATB2 Mediates H3K9 Delactylation by Recruiting HDAC3 to Repress LCN2 and Inhibit Lung Tumor Growth and Metastasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lactylation and acetylation: parallel paths, divergent deeds, and research dilemmas.Journal of translational medicine · 2026Review
- Integrated epigenetic networks in aging: from histone to RNA modifications.Journal of translational medicine · 2026Review
- Lactylation in pulmonary fibrosis: current understanding and challenges.Journal of translational medicine · 2026Review
- Clinical Outcomes of an Innovative Poly-L-Lactic Acid (LASYNPRO) in Facial Rejuvenation: Prospective, Multicenter Spanish Study.Journal of cosmetic dermatology · 2026Article
- Preparation of Uniform PEG-PLLA Microspheres via Membrane Emulsification for Soft Tissue Filling Applications.Journal of functional biomaterials · 2026Article
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Authors and funding
12 authors.
Funding
Abstract
The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further investigation. This study demonstrates that the depletion of macrophages mitigates the stimulating effect of lactate on collagen synthesis in fibroblasts. Through joint CUT&Tag and RNA-sequencing analyses, a feedback loop between H4K12 lactylation (H4K12la) and histone deacetylase 3 (HDAC3) in macrophages that drives lactate-induced collagen synthesis are identified. Macrophages can uptake extracellular lactate via monocarboxylate transporter-1 (MCT1), leading to an up-regulation of H4K12la levels through a KAT5-KAT8-dependent mechanism in response to Poly-L-Lactic Acid (PLLA) stimulation, a source of low concentration and persistent lactate, thereby promoting collagen synthesis in fibroblasts. Furthermore, H4K12la is enriched at the promoters of TGF-β1 and TGF-β3, enhancing their transcription. Hyperlactylation of H4K12la inhibits the expression of the eraser HDAC3, while the activation of HDAC3 reduces H4K12la in macrophages and suppresses collagen synthesis in fibroblasts. In conclusion, this study illustrates that macrophages play a critical role in lactate-induced collagen synthesis in the skin, and targeting the lactate-H4K12la-HDAC3-TGF-β axis may represent a novel approach for enhancing collagen production to combat skin aging.
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