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  4. Vol 8, Issue 1, 2026

The Post-Translational Code of Myocardial Fibrosis: From Signaling Circuitry to Epigenetic Consolidation

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DOI: 10.23977/medcm.2026.080107 | Downloads: 4 | Views: 61

Author(s)

Weijun Li 1, Zhixi Hu 1

Affiliation(s)

1 Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China

Corresponding Author

Zhixi Hu

ABSTRACT

The onset and progression of heart failure (HF) are primarily driven by myocardial fibrosis (MF), a key pathological process. However, previous studies have largely focused on interventions targeting single signaling pathways, yielding limited clinical efficacy and highlighting the limitations of conventional therapies. Currently, the academic community is shifting its focus to "post-translational modifications"—deep regulatory mechanisms that transcend the genomic template—which are considered key factors contributing to the complexity and irreversibility of MF. This article first explores the mechanisms underlying MF signaling in a layered manner: centered on the TGF-β/Smad core axis, various signaling pathways—including MAPK, PI3K/AKT, and NF-κB—interact to form a highly integrated signaling network, rather than targeting a single pathway. Building on this foundation, we conduct an in-depth analysis of the critical role of site-specific post-translational modifications (PTMs) in this process. Phosphorylation, acetylation, ubiquitination, and the emerging lactylation (Kla) are no longer merely biochemical modifications; rather, they interact with one another to jointly determine protein function and fate. By analyzing synergistic or antagonistic interactions at key lysine residues (e.g., SERCA2a K480, α-MHC K1897), this study proposes the "metabolic epigenetic imprinting" model. This model provides a rational explanation for how "transient stress" is converted into permanent cardiac structural fibrosis through "biochemical imprinting." Finally, we summarize the shift from traditional drug therapy to precision PTM editing as a therapeutic approach and, based on the PTM profile, elucidate how to achieve better therapeutic outcomes, aiming to provide a substantial theoretical foundation for subsequent research on reversing cardiac remodeling.

KEYWORDS

Myocardial fibrosis; post-translational modifications (PTMs); transforming growth factor-β/Smad signaling pathway; lysine lactylation; cross-regulation and competitive interactions; metabolic-epigenetic axis; cardiac remodeling

CITE THIS PAPER

Weijun Li, Zhixi Hu. The Post-Translational Code of Myocardial Fibrosis: From Signaling Circuitry to Epigenetic Consolidation. MEDS Chinese Medicine (2026). Vol. 8, No. 1, 54-62. DOI: http://dx.doi.org/10.23977/medcm.2026.080107.

REFERENCES

[1] McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021. 42(36): 3599-3726.
[2] Greene SJ, Butler J, Fonarow GC. Contextualizing Risk Among Patients With Heart Failure. JAMA. 2021. 326(22): 2261-2262.
[3] Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021. 143(8): e254-e743.
[4] Taylor CJ, Ordóñez-Mena JM, Roalfe AK, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. BMJ. 2019. 364: l223.
[5] Bacmeister L, Schwarzl M, Warnke S, et al. Inflammation and fibrosis in murine models of heart failure. BASIC RESEARCH IN CARDIOLOGY. 2019. 114(3).
[6] Ghazal R, Wang M, Liu D, Tschumperlin DJ, Pereira NL. Cardiac Fibrosis in the Multi-Omics Era: Implications for Heart Failure. Circ Res. 2025. 136(7): 773-802.
[7] Cui XK, Wang JX, Li K, Lv BS, Hou BK, Ding ZJ. Protein post-translational modifications in auxin signaling. Journal of Genetics and Genomics. 2024. 51(3): 279-291.
[8] Wethekam LC, Moore JK. Microtubule cytoskeleton: Revealing new readers of the tubulin code. Curr Biol. 2022. 32(18): R960-R962.
[9] Miao RR, Wang LB, Chen ZG, et al. Advances in the study of nicotinamide adenine dinucleotide phosphate oxidase in myocardial remodeling. Frontiers in Cardiovascular Medicine. 2022. 9.
[10] Wu D, Liu T. Studying Reversible Protein Post-translational Modification through Co-translational Modification. CHEMBIOCHEM. 2023 .
[11] Campbell SL, Philips MR. Post-translational modification of RAS proteins. Curr Opin Struct Biol. 2021. 71: 180-192.
[12] Zhao X, Kwan J, Yip K, Liu PP, Liu FF. Targeting metabolic dysregulation for fibrosis therapy. Nat Rev Drug Discov. 2020. 19(1): 57-75.
[13] Wu X, Yang Y. Neutrophil extracellular traps (NETs) and fibrotic diseases. Int Immunopharmacol. 2024. 133: 112085.
[14] Kania G, Lindner D, Zuppinger C. Editorial: Myocardial fibrosis: What we know now. Frontiers in Cardiovascular Medicine. 2023. 9.
[15] Chen TT, Xiao F, Li N, et al. Inflammasome as an Effective Platform for Fibrosis Therapy. J Inflamm Res. 2021. 14: 1575-1590.
[16] Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021. 117(6): 1450-1488.
[17] Zhang YL, Li PB, Han X, Zhang B, Li HH. Blockage of Fibronectin 1 Ameliorates Myocardial Ischemia/Reperfusion Injury in Association with Activation of AMP-LKB1-AMPK Signaling Pathway. Oxid Med Cell Longev. 2022. 2022: 6196173.
[18] Zhang QJ, He Y, Li YN, Liao J, Zang QS, Liu ZP. Matricellular Protein Cilp1 Promotes Myocardial Fibrosis In Response To Myocardial Infarction. CIRCULATION RESEARCH. 2022. 131.
[19] Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020. 587(7835): 555-566.
[20] Buechler MB, Pradhan RN, Krishnamurty AT, et al. Cross-tissue organization of the fibroblast lineage. Nature. 2021. 593(7860): 575-579.
[21] Yoshida GJ. Regulation of heterogeneous cancer-associated fibroblasts: the molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020. 39(1): 112.
[22] Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb Perspect Biol. 2016. 8(5): a021873.
[23] Peng D, Fu M, Wang M, Wei Y, Wei X. Targeting TGF-β signal transduction for fibrosis and cancer therapy. Mol Cancer. 2022. 21(1): 104.
[24] Modi SJ, Kulkarni VM. Discovery of VEGFR-2 inhibitors exerting significant anticancer activity against CD44+ and CD133+ cancer stem cells (CSCs): Reversal of TGF-β induced epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma. Eur J Med Chem. 2020. 207: 112851.
[25] Zhang T, He X, Caldwell L, et al. NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling. Sci Transl Med. 2022. 14(637): eaaz4028.
[26] Alyaseer A, de Lima M, Braga TT. The Role of NLRP3 Inflammasome Activation in the Epithelial to Mesenchymal Transition Process During the Fibrosis. Front Immunol. 2020. 11: 883.
[27] Yu J, Zhao X, Yan X, et al. Aloe-emodin ameliorated MI-induced cardiac remodeling in mice via inhibiting TGF-β/SMAD signaling via up-regulating SMAD7. Phytomedicine. 2023. 114: 154793.
[28] Zheng L, Liang H, Zhang Q, et al. circPTEN1, a circular RNA generated from PTEN, suppresses cancer progression through inhibition of TGF-β/Smad signaling. Mol Cancer. 2022. 21(1): 41.
[29] Deng Z, Fan T, Xiao C, et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024. 9(1): 61.
[30] Martin CJ, Datta A, Littlefield C, et al. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020. 12(536): eaay8456.
[31] Cully M. TGFβ1-specific antibody spurs anti-tumour immunity. Nat Rev Drug Discov. 2020. 19(5): 310.
[32] Singh R, Kaundal RK, Zhao B, Bouchareb R, Lebeche D. Resistin induces cardiac fibroblast-myofibroblast differentiation through JAK/STAT3 and JNK/c-Jun signaling. Pharmacol Res. 2021. 167: 105414.
[33] Wang J, Deng B, Liu Q, et al. Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload. Cell Death Dis. 2020. 11(7): 574.
[34] Sun Z, Ji Z, Meng H, et al. Lactate facilitated mitochondrial fission-derived ROS to promote pulmonary fibrosis via ERK/DRP-1 signaling. J Transl Med. 2024. 22(1): 479.
[35] Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023. 8(1): 333.
[36] Meng H, Du Z, Lu W, et al. Baoyuan decoction (BYD) attenuates cardiac hypertrophy through ANKRD1-ERK/GATA4 pathway in heart failure after acute myocardial infarction. Phytomedicine. 2021. 89: 153617.
[37] Suthahar N, Meijers WC, Silljé H, de Boer RA. From Inflammation to Fibrosis-Molecular and Cellular Mechanisms of Myocardial Tissue Remodelling and Perspectives on Differential Treatment Opportunities. Curr Heart Fail Rep. 2017. 14(4): 235-250.
[38] Yin C, Ye Z, Wu J, et al. Elevated Wnt2 and Wnt4 activate NF-κB signaling to promote cardiac fibrosis by cooperation of Fzd4/2 and LRP6 following myocardial infarction. EBioMedicine. 2021. 74: 103745.
[39] Dai C, Luo W, Chen Y, et al. Tabersonine attenuates Angiotensin II-induced cardiac remodeling and dysfunction through targeting TAK1 and inhibiting TAK1-mediated cardiac inflammation. Phytomedicine. 2022. 103: 154238.
[40] Ding W, Feng H, Li WJ, et al. Apocynin attenuates diabetic cardiomyopathy by suppressing ASK1-p38/JNK signaling. Eur J Pharmacol. 2021. 909: 174402.
[41] Huang J, Chen L, Wu J, et al. Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions. J Med Chem. 2022. 65(24): 16033-16061.
[42] Qin W, Cao L, Massey IY. Role of PI3K/Akt signaling pathway in cardiac fibrosis. Mol Cell Biochem. 2021. 476(11): 4045-4059.
[43] Zhang T, Li L, Mo X, et al. Matairesinol blunts adverse cardiac remodeling and heart failure induced by pressure overload by regulating Prdx1 and PI3K/AKT/FOXO1 signaling. Phytomedicine. 2024. 135: 156054.
[44] Chen X, Zhang Z, Zhang X, et al. Paeonol attenuates heart failure induced by transverse aortic constriction via ERK1/2 signalling. Pharm Biol. 2022. 60(1): 562-569.
[45] Wang X, Chen L, Zhao X, et al. A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα. Cell Death Dis. 2020. 11(2): 96.
[46] Cui Y, Wu J, Wang Y, et al. Protective effects of ginsenoside F(2) on isoproterenol-induced myocardial infarction by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways. Phytomedicine. 2024. 129: 155637.
[47] Alsereidi FR, Khashim Z, Marzook H, et al. Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells. Cardiovasc Diabetol. 2024. 23(1): 388.
[48] Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. NATURE REVIEWS MOLECULAR CELL BIOLOGY. 2012. 13(4): 251-262.
[49] Bilbrough T, Piemontese E, Seitz O. Dissecting the role of protein phosphorylation: a chemical biology toolbox. Chem Soc Rev. 2022. 51(13): 5691-5730.
[50] Li C, Meng X, Wang L, Dai X. Mechanism of action of non-coding RNAs and traditional Chinese medicine in myocardial fibrosis: Focus on the TGF-β/Smad signaling pathway. Front Pharmacol. 2023. 14: 1092148.
[51] Huang S, Chen B, Humeres C, Alex L, Hanna A, Frangogiannis NG. The role of Smad2 and Smad3 in regulating homeostatic functions of fibroblasts in vitro and in adult mice. Biochim Biophys Acta Mol Cell Res. 2020. 1867(7): 118703.
[52] Li JH, Yousefi K, Ding W, Singh J, Shehadeh LA. Osteopontin RNA aptamer can prevent and reverse pressure overload-induced heart failure. CARDIOVASCULAR RESEARCH. 2017. 113(6): 633-643.
[53] Traub J, Otto M, Monoranu CM, et al. Increasing Phosphorylated Tau Protein Serum Levels in the Course of Chronic Heart Failure. JACC Heart Fail. 2024. 12(8): 1494-1496.
[54] Pizzo E, Cervantes DO, Ketkar H, et al. Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy. Am J Physiol Heart Circ Physiol. 2024. 326(6): H1424-H1445.
[55] Kampourakis T, Ponnam S, Campbell KS, Wellette-Hunsucker A, Koch D. Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities. Nat Commun. 2024. 15(1): 5111.
[56] Dobrev D, Wehrens XH. Role of RyR2 phosphorylation in heart failure and arrhythmias: Controversies around ryanodine receptor phosphorylation in cardiac disease. Circ Res. 2014. 114(8): 1311-1319.
[57] Schmeckpeper J, Kim K, George SA, et al. RyR2 inhibition with dantrolene is antiarrhythmic, prevents further pathological remodeling, and improves cardiac function in chronic ischemic heart disease. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY. 2023. 181: 67-78.
[58] Sun M, Zhang X. Current methodologies in protein ubiquitination characterization: from ubiquitinated protein to ubiquitin chain architecture. Cell Biosci. 2022. 12(1): 126.
[59] Varejão N, Lascorz J, Li Y, Reverter D. Molecular mechanisms in SUMO conjugation. Biochem Soc Trans. 2020. 48(1): 123-135.
[60] Sheng Z, Zhu J, Deng YN, Gao S, Liang S. SUMOylation modification-mediated cell death. Open Biol. 2021. 11(7): 210050.
[61] Wright KM, Nathan S, Jiang H, et al. NEDD4L intramolecular interactions regulate its auto and substrate Na(V)1.5 ubiquitination. J Biol Chem. 2024. 300(3): 105715.
[62] Zhang N, Zhang Y, Qian H, Wu S, Cao L, Sun Y. Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling. Cell Death Differ. 2020. 27(9): 2605-2619.
[63] Yuan L, Bu S, Du M, et al. RNF207 exacerbates pathological cardiac hypertrophy via post-translational modification of TAB1. Cardiovasc Res. 2023. 119(1): 183-194.
[64] Lei Q, Yi T, Li H, et al. Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78). Sci Rep. 2020. 10(1): 10604.
[65] Samuel TJ, Rosenberry RP, Lee S, Pan Z. Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy. Int J Mol Sci. 2018. 19(4): 1086.
[66] Hu W, Xu T, Wu P, et al. Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca(2+)-ATPase 2a. Sci Rep. 2017. 7: 41017.
[67] Su Q, Chen X, Ling X, et al. SUMOylation of Smad2 mediates TGF-β-regulated endothelial-mesenchymal transition. J Biol Chem. 2023. 299(10): 105244.

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