Research progress on lactylation modification in pathogenesis of osteoarthritis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WU Yuangang , SUN Kaibo , DING Yang , LI Mingyang , LIU Yuan , WU Limin , PENG Linbo ,  SHEN Bin

Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding?author：

SHEN Bin, Email: shenbin_1971@163.com

Keywords：

Lactylation modification; osteoarthritis; chondrocytes; synoviocytes; immune cells; epigenetics

DOI：

10.7507/1002-1892.202508077

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress on lactylation modification in the pathogenesis of osteoarthritis (OA). Methods Relevant studies published in recent years on lactate metabolism and lactylation modification in OA were retrieved and analyzed, summarizing the molecular mechanisms of lactylation and its regulatory roles in different cells and pathological processes. Results Lactate, as the major metabolic product of glycolysis, not only participates in energy metabolism but also plays a crucial role in OA progression through lactylation modification. Lactate-driven histone and non-histone lactylation regulate gene transcription and cellular functions, contributing to chondrocyte metabolic reprogramming, extracellular matrix (ECM) synthesis and degradation, cell proliferation and apoptosis, as well as ferroptosis. In fibroblast-like synoviocytes, lactylation modification promotes cellular senescence and the release of inflammatory factors; in immune cells, lactylation regulates inflammatory responses by influencing macrophage polarization and intercellular communication. Overall, lactylation modification exhibits a dual effect in OA: it aggravates ECM degradation and inflammation on the one hand, but under specific microenvironments, it also promotes repair and regeneration. However, the site-specificity, cell-type heterogeneity, and cross-talk of lactylation with other epigenetic modifications remain to be further clarified. Conclusion Lactylation modification provides a novel perspective for understanding the metabolic and epigenetic mechanisms of OA and may serve as a potential biomarker and therapeutic target. Future studies combining multi-omics approaches to map the global lactylation landscape, together with small-molecule inhibitors, epigenetic editing tools, and regenerative medicine strategies, may enable precise regulation of lactylation, offering new strategies to delay or even reverse OA progression.

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3.	Wu Y, Li J, Zeng Y, et al. Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies. Int J Oral Sci, 2022, 14(1): 40. doi: 10.1038/s41368-022-00187-z.
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7.	Roos EM, Arden NK. Strategies for the prevention of knee osteoarthritis. Nat Rev Rheumatol, 2016, 12(2): 92-101.
8.	Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage, 2019, 27(11): 1578-1589.
9.	Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol, 2020, 16(12): 673-688.
10.	Zheng L, Zhang Z, Sheng P, et al. The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev, 2021, 66: 101249. doi: 10.1016/j.arr.2020.101249.
11.	Qi Z, Zhu J, Cai W, et al. The role and intervention of mitochondrial metabolism in osteoarthritis. Mol Cell Biochem, 2024, 479(6): 1513-1524.
12.	Gomez-Contreras PC, Kluz PN, Hines MR, et al. Intersections between mitochondrial metabolism and redox biology mediate posttraumatic osteoarthritis. Curr Rheumatol Rep, 2021, 23(5): 32. doi: 10.1007/s11926-021-00994-z.
13.	Sampath SJP, Venkatesan V, Ghosh S, et al. Obesity, metabolic syndrome, and osteoarthritis-an updated review. Curr Obes Rep, 2023, 12(3): 308-331.
14.	Certo M, Llibre A, Lee W, et al. Understanding lactate sensing and signalling. Trends Endocrinol Metab, 2022, 33(10): 722-735.
15.	Chen L, Huang L, Gu Y, et al. Lactate-lactylation hands between metabolic reprogramming and immunosuppression. Int J Mol Sci, 2022, 23(19): 11943. doi: 10.3390/ijms231911943.
16.	Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther, 2022, 7(1): 305. doi: 10.1038/s41392-022-01151-3.
17.	Chen J, Huang Z, Chen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther, 2025, 10(1): 38. doi: 10.1038/s41392-024-02082-x.
18.	Li R, Yang Y, Wang H, et al. Lactate and lactylation in the brain: current progress and perspectives. Cell Mol Neurobiol, 2023, 43(6): 2541-2555.
19.	Huang Y, Yue S, Yan Z, et al. Lactate-upregulated ARG2 expression induces cellular senescence in fibroblast-like synoviocytes of osteoarthritis via activating the mTOR/S6K1 signaling pathway. Int Immunopharmacol, 2024, 142(Pt A): 113071. doi: 10.1016/j.intimp.2024.113071.
20.	Huang YF, Wang G, Ding L, et al. Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. Redox Biol, 2023, 67: 102867. doi: 10.1016/j.redox.2023.102867.
21.	Yu X, Yang J, Xu J, et al. Histone lactylation: from tumor lactate metabolism to epigenetic regulation. Int J Biol Sci, 2024, 20(5): 1833-1854.
22.	Xie Y, Hu H, Liu M, et al. The role and mechanism of histone lactylation in health and diseases. Front Genet, 2022, 13: 949252. doi: 10.3389/fgene.2022.949252.
23.	Xia J, Qiao Z, Hao X, et al. LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene. Autoimmunity, 2024, 57(1): 2384889. doi: 10.1080/08916934.2024.2384889.
24.	Lan W, Chen X, Yu H, et al. UGDH Lactylation aggravates osteoarthritis by suppressing glycosaminoglycan synthesis and orchestrating nucleocytoplasmic transport to activate MAPK signaling. Adv Sci (Weinh), 2025, 12(20): e2413709. doi: 10.1002/advs.202413709.
25.	Ye L, Jiang Y, Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev, 2022, 68: 81-92.
26.	Lin Y, Wang Y, Li PF. Mutual regulation of lactate dehydrogenase and redox robustness. Front Physiol, 2022, 13: 1038421. doi: 10.3389/fphys.2022.1038421.
27.	Pouysségur J, Marchiq I, Parks SK, et al. ‘Warburg effect’ controls tumor growth, bacterial, viral infections and immunity- Genetic deconstruction and therapeutic perspectives. Semin Cancer Biol, 2022, 86(Pt 2): 334-346.
28.	Xu B, Liu Y, Li N, et al. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol, 2024, 15: 1395786. doi: 10.3389/fimmu.2024.1395786.
29.	Zhang M, Kong X, Wu C, et al. The role of lactate and lactylation in ischemic cardiomyopathy: Mechanisms and gene expression. Exp Mol Pathol, 2025, 141: 104957. doi: 10.1016/j.yexmp.2025.104957.
30.	Zhao L, Qi H, Lv H, et al. Lactylation in health and disease: physiological or pathological? Theranostics, 2025, 15(5): 1787-1821. doi: 10.7150/thno.105353.
31.	Nian F, Qian Y, Xu F, et al. LDHA promotes osteoblast differentiation through histone lactylation. Biochem Biophys Res Commun, 2022, 615: 31-35.
32.	Luan S, Luan J. A multidimensional approach reveals the function of lactylation related genes in osteoarthritis. Sci Rep, 2025, 15(1): 7743. doi: 10.1038/s41598-025-89072-3.
33.	Zhang Y, Zhao CY, Zhou Z, et al. The effect of lactate dehydrogenase B and its mediated histone lactylation on chondrocyte ferroptosis during osteoarthritis. J Orthop Surg Res, 2025, 20(1): 493. doi: 10.1186/s13018-025-05894-x.
34.	Yang B, Li Z, Yang Z, et al. Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration. Nat Commun, 2025, 16(1): 2711. doi: 10.1038/s41467-025-57779-6.
35.	Knights AJ, Redding SJ, Maerz T. Inflammation in osteoarthritis: the latest progress and ongoing challenges. Curr Opin Rheumatol, 2023, 35(2): 128-134.
36.	Dainese P, Wyngaert KV, De Mits S, et al. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Osteoarthritis Cartilage, 2022, 30(4): 516-534.
37.	Adam MS, Zhuang H, Ren X, et al. The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis. Front Endocrinol (Lausanne), 2024, 15: 1393550. doi: 10.3389/fendo.2024.1393550.
38.	Yang Y, Shi J, Yu J, et al. New posttranslational modification lactylation brings new inspiration for the treatment of rheumatoid arthritis. J Inflamm Res, 2024, 17: 11845-11860.
39.	Hu J, Jin Z, Gao Y, et al. Global profiling of lactylation proteomics and specific lactylated site validation in rheumatoid arthritis patients. J Proteome Res, 2025, 24(4): 1732-1744.
40.	Liu W, Yang R, Zhan Y, et al. Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming. Front Immunol, 2025, 16: 1589853. doi: 10.3389/fimmu.2025.1589853.
41.	Arra M, Swarnkar G, Ke K, et al. LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis. Nat Commun, 2020, 11(1): 3427. doi: 10.1038/s41467-020-17242-0.
42.	韋艷, 田艾. 乳酸/乳酸化修飾調控巨噬細胞參與牙周病發生的研究進展. 口腔醫學研究, 2024, 40(7): 578-582.
43.	Rahmati M, Nalesso G, Mobasheri A, et al. Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res Rev, 2017, 40: 20-30.
44.	Fu B, Shen J, Zou X, et al. Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Res, 2024, 12(1): 32. doi: 10.1038/s41413-024-00333-9.
45.	Miao Y, Chen Y, Xue F, et al. Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression. EBioMedicine, 2022, 76: 103847. doi: 10.1016/j.ebiom.2022.103847.
46.	Guo Z, Lin J, Sun K, et al. Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway. Front Pharmacol, 2022, 13: 791376. doi: 10.3389/fphar.2022.791376.
47.	Jahr H. HDACi and Nrf2: not from alpha to omega but from acetylation to OA. Arthritis Res Ther, 2015, 17: 381. doi: 10.1186/s13075-015-0885-x.
48.	Fu Y, Kinter M, Hudson J, et al. Aging promotes sirtuin 3-dependent cartilage superoxide dismutase 2 acetylation and osteoarthritis. Arthritis Rheumatol, 2016, 68(8): 1887-1898.
49.	Assi R, Cherifi C, Cornelis FMF, et al. Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis. Ann Rheum Dis, 2023, 82(7): 963-973.
50.	Zheng H, Aihaiti Y, Cai Y, et al. The m6A/m1A/m5C-related methylation modification patterns and immune landscapes in rheumatoid arthritis and osteoarthritis revealed by microarray and single-cell transcriptome. J Inflamm Res, 2023, 16: 5001-5025.
51.	An S, Yao Y, Hu H, et al. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. Cell Death Dis, 2023, 14(7): 457. doi: 10.1038/s41419-023-05952-4.
52.	Wang X, Fan W, Li N, et al. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2. Genome Biol, 2023, 24(1): 87. doi: 10.1186/s13059-023-02931-y.

1. Jiang Y. Osteoarthritis year in review 2021: biology. Osteoarthritis Cartilage, 2022, 30(2): 207-215.
2. Wu Y, Sun K, Li M, et al. LRP1 mediates endocytosis activity and is a potential therapeutic target in osteoarthritis. Orthop Surg, 2025, 17(6): 1604-1619.
3. Wu Y, Li J, Zeng Y, et al. Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies. Int J Oral Sci, 2022, 14(1): 40. doi: 10.1038/s41368-022-00187-z.
4. Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: A review. JAMA, 2021, 325(6): 568-578.
5. Tang S, Zhang C, Oo WM, et al. Osteoarthritis. Nat Rev Dis Primers, 2025, 11(1): 10. doi: 10.1038/s41572-025-00594-6.
6. GBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990-2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol, 2023, 5(9): e508-e522.
7. Roos EM, Arden NK. Strategies for the prevention of knee osteoarthritis. Nat Rev Rheumatol, 2016, 12(2): 92-101.
8. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage, 2019, 27(11): 1578-1589.
9. Latourte A, Kloppenburg M, Richette P. Emerging pharmaceutical therapies for osteoarthritis. Nat Rev Rheumatol, 2020, 16(12): 673-688.
10. Zheng L, Zhang Z, Sheng P, et al. The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. Ageing Res Rev, 2021, 66: 101249. doi: 10.1016/j.arr.2020.101249.
11. Qi Z, Zhu J, Cai W, et al. The role and intervention of mitochondrial metabolism in osteoarthritis. Mol Cell Biochem, 2024, 479(6): 1513-1524.
12. Gomez-Contreras PC, Kluz PN, Hines MR, et al. Intersections between mitochondrial metabolism and redox biology mediate posttraumatic osteoarthritis. Curr Rheumatol Rep, 2021, 23(5): 32. doi: 10.1007/s11926-021-00994-z.
13. Sampath SJP, Venkatesan V, Ghosh S, et al. Obesity, metabolic syndrome, and osteoarthritis-an updated review. Curr Obes Rep, 2023, 12(3): 308-331.
14. Certo M, Llibre A, Lee W, et al. Understanding lactate sensing and signalling. Trends Endocrinol Metab, 2022, 33(10): 722-735.
15. Chen L, Huang L, Gu Y, et al. Lactate-lactylation hands between metabolic reprogramming and immunosuppression. Int J Mol Sci, 2022, 23(19): 11943. doi: 10.3390/ijms231911943.
16. Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther, 2022, 7(1): 305. doi: 10.1038/s41392-022-01151-3.
17. Chen J, Huang Z, Chen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther, 2025, 10(1): 38. doi: 10.1038/s41392-024-02082-x.
18. Li R, Yang Y, Wang H, et al. Lactate and lactylation in the brain: current progress and perspectives. Cell Mol Neurobiol, 2023, 43(6): 2541-2555.
19. Huang Y, Yue S, Yan Z, et al. Lactate-upregulated ARG2 expression induces cellular senescence in fibroblast-like synoviocytes of osteoarthritis via activating the mTOR/S6K1 signaling pathway. Int Immunopharmacol, 2024, 142(Pt A): 113071. doi: 10.1016/j.intimp.2024.113071.
20. Huang YF, Wang G, Ding L, et al. Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. Redox Biol, 2023, 67: 102867. doi: 10.1016/j.redox.2023.102867.
21. Yu X, Yang J, Xu J, et al. Histone lactylation: from tumor lactate metabolism to epigenetic regulation. Int J Biol Sci, 2024, 20(5): 1833-1854.
22. Xie Y, Hu H, Liu M, et al. The role and mechanism of histone lactylation in health and diseases. Front Genet, 2022, 13: 949252. doi: 10.3389/fgene.2022.949252.
23. Xia J, Qiao Z, Hao X, et al. LDHA-induced histone lactylation mediates the development of osteoarthritis through regulating the transcription activity of TPI1 gene. Autoimmunity, 2024, 57(1): 2384889. doi: 10.1080/08916934.2024.2384889.
24. Lan W, Chen X, Yu H, et al. UGDH Lactylation aggravates osteoarthritis by suppressing glycosaminoglycan synthesis and orchestrating nucleocytoplasmic transport to activate MAPK signaling. Adv Sci (Weinh), 2025, 12(20): e2413709. doi: 10.1002/advs.202413709.
25. Ye L, Jiang Y, Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev, 2022, 68: 81-92.
26. Lin Y, Wang Y, Li PF. Mutual regulation of lactate dehydrogenase and redox robustness. Front Physiol, 2022, 13: 1038421. doi: 10.3389/fphys.2022.1038421.
27. Pouysségur J, Marchiq I, Parks SK, et al. ‘Warburg effect’ controls tumor growth, bacterial, viral infections and immunity- Genetic deconstruction and therapeutic perspectives. Semin Cancer Biol, 2022, 86(Pt 2): 334-346.
28. Xu B, Liu Y, Li N, et al. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol, 2024, 15: 1395786. doi: 10.3389/fimmu.2024.1395786.
29. Zhang M, Kong X, Wu C, et al. The role of lactate and lactylation in ischemic cardiomyopathy: Mechanisms and gene expression. Exp Mol Pathol, 2025, 141: 104957. doi: 10.1016/j.yexmp.2025.104957.
30. Zhao L, Qi H, Lv H, et al. Lactylation in health and disease: physiological or pathological? Theranostics, 2025, 15(5): 1787-1821. doi: 10.7150/thno.105353.
31. Nian F, Qian Y, Xu F, et al. LDHA promotes osteoblast differentiation through histone lactylation. Biochem Biophys Res Commun, 2022, 615: 31-35.
32. Luan S, Luan J. A multidimensional approach reveals the function of lactylation related genes in osteoarthritis. Sci Rep, 2025, 15(1): 7743. doi: 10.1038/s41598-025-89072-3.
33. Zhang Y, Zhao CY, Zhou Z, et al. The effect of lactate dehydrogenase B and its mediated histone lactylation on chondrocyte ferroptosis during osteoarthritis. J Orthop Surg Res, 2025, 20(1): 493. doi: 10.1186/s13018-025-05894-x.
34. Yang B, Li Z, Yang Z, et al. Recapitulating hypoxic metabolism in cartilaginous organoids via adaptive cell-matrix interactions enhances histone lactylation and cartilage regeneration. Nat Commun, 2025, 16(1): 2711. doi: 10.1038/s41467-025-57779-6.
35. Knights AJ, Redding SJ, Maerz T. Inflammation in osteoarthritis: the latest progress and ongoing challenges. Curr Opin Rheumatol, 2023, 35(2): 128-134.
36. Dainese P, Wyngaert KV, De Mits S, et al. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Osteoarthritis Cartilage, 2022, 30(4): 516-534.
37. Adam MS, Zhuang H, Ren X, et al. The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis. Front Endocrinol (Lausanne), 2024, 15: 1393550. doi: 10.3389/fendo.2024.1393550.
38. Yang Y, Shi J, Yu J, et al. New posttranslational modification lactylation brings new inspiration for the treatment of rheumatoid arthritis. J Inflamm Res, 2024, 17: 11845-11860.
39. Hu J, Jin Z, Gao Y, et al. Global profiling of lactylation proteomics and specific lactylated site validation in rheumatoid arthritis patients. J Proteome Res, 2025, 24(4): 1732-1744.
40. Liu W, Yang R, Zhan Y, et al. Lactate and lactylation: emerging roles in autoimmune diseases and metabolic reprogramming. Front Immunol, 2025, 16: 1589853. doi: 10.3389/fimmu.2025.1589853.
41. Arra M, Swarnkar G, Ke K, et al. LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis. Nat Commun, 2020, 11(1): 3427. doi: 10.1038/s41467-020-17242-0.
42. 韋艷, 田艾. 乳酸/乳酸化修飾調控巨噬細胞參與牙周病發生的研究進展. 口腔醫學研究, 2024, 40(7): 578-582.
43. Rahmati M, Nalesso G, Mobasheri A, et al. Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res Rev, 2017, 40: 20-30.
44. Fu B, Shen J, Zou X, et al. Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Res, 2024, 12(1): 32. doi: 10.1038/s41413-024-00333-9.
45. Miao Y, Chen Y, Xue F, et al. Contribution of ferroptosis and GPX4’s dual functions to osteoarthritis progression. EBioMedicine, 2022, 76: 103847. doi: 10.1016/j.ebiom.2022.103847.
46. Guo Z, Lin J, Sun K, et al. Deferoxamine alleviates osteoarthritis by inhibiting chondrocyte ferroptosis and activating the Nrf2 pathway. Front Pharmacol, 2022, 13: 791376. doi: 10.3389/fphar.2022.791376.
47. Jahr H. HDACi and Nrf2: not from alpha to omega but from acetylation to OA. Arthritis Res Ther, 2015, 17: 381. doi: 10.1186/s13075-015-0885-x.
48. Fu Y, Kinter M, Hudson J, et al. Aging promotes sirtuin 3-dependent cartilage superoxide dismutase 2 acetylation and osteoarthritis. Arthritis Rheumatol, 2016, 68(8): 1887-1898.
49. Assi R, Cherifi C, Cornelis FMF, et al. Inhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis. Ann Rheum Dis, 2023, 82(7): 963-973.
50. Zheng H, Aihaiti Y, Cai Y, et al. The m6A/m1A/m5C-related methylation modification patterns and immune landscapes in rheumatoid arthritis and osteoarthritis revealed by microarray and single-cell transcriptome. J Inflamm Res, 2023, 16: 5001-5025.
51. An S, Yao Y, Hu H, et al. PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation. Cell Death Dis, 2023, 14(7): 457. doi: 10.1038/s41419-023-05952-4.
52. Wang X, Fan W, Li N, et al. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2. Genome Biol, 2023, 24(1): 87. doi: 10.1186/s13059-023-02931-y.

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Latest ArticlesResearch progress on lactylation modification in pathogenesis of osteoarthritis

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