A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling
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...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411408 |
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| author | Ying Zou Mibu Cao Meiling Tai Haoxian Zhou Li Tao Shu Wu Kaiye Yang Youliang Zhang Yuanlong Ge Hao Wang Shengkang Luo Zhenyu Ju |
| author_facet | Ying Zou Mibu Cao Meiling Tai Haoxian Zhou Li Tao Shu Wu Kaiye Yang Youliang Zhang Yuanlong Ge Hao Wang Shengkang Luo Zhenyu Ju |
| author_sort | Ying Zou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ee7dfe67b7fc45bf8865b22de2fee273 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-ee7dfe67b7fc45bf8865b22de2fee2732025-08-20T03:16:56ZengWileyAdvanced Science2198-38442025-04-011213n/an/a10.1002/advs.202411408A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β SignalingYing Zou0Mibu Cao1Meiling Tai2Haoxian Zhou3Li Tao4Shu Wu5Kaiye Yang6Youliang Zhang7Yuanlong Ge8Hao Wang9Shengkang Luo10Zhenyu Ju11Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaDepartment of Plastic and Reconstructive Surgery Guangdong Second Provincial General Hospital Jinan University Guangzhou 510403 ChinaR&D Center Infinitus (China) Company Ltd Guangzhou 510640 ChinaDepartment of Cardiology Guangdong Provincial Cardiovascular Institute Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510080 ChinaKey Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaKey Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaR&D Center Infinitus (China) Company Ltd Guangzhou 510640 ChinaDepartment of Plastic and Reconstructive Surgery Guangdong Second Provincial General Hospital Jinan University Guangzhou 510403 ChinaKey Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaDepartment of Anesthesiology The First Affiliated Hospital Jinan University Guangzhou 510632 ChinaKey Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaKey Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 ChinaAbstract 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.https://doi.org/10.1002/advs.202411408collagen synthesisfibroblastsH4K12 lactylationlactatemacrophages |
| spellingShingle | Ying Zou Mibu Cao Meiling Tai Haoxian Zhou Li Tao Shu Wu Kaiye Yang Youliang Zhang Yuanlong Ge Hao Wang Shengkang Luo Zhenyu Ju A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling Advanced Science collagen synthesis fibroblasts H4K12 lactylation lactate macrophages |
| title | A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling |
| title_full | A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling |
| title_fullStr | A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling |
| title_full_unstemmed | A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling |
| title_short | A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling |
| title_sort | feedback loop driven by h4k12 lactylation and hdac3 in macrophages regulates lactate induced collagen synthesis in fibroblasts via the tgf β signaling |
| topic | collagen synthesis fibroblasts H4K12 lactylation lactate macrophages |
| url | https://doi.org/10.1002/advs.202411408 |
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