15 November 2025: Review Articles
Signaling Pathways and Therapeutic Approaches in Post-Myocardial Infarction Fibrosis
Gen Ba ABCDEF 1*, Meiqiong Chen G 1
DOI: 10.12659/MSM.949030
Med Sci Monit 2025; 31:e949030
Abstract
ABSTRACT: Myocardial infarction (MI) is a leading cause of myocardial fibrosis, contributing significantly to heart disease morbidity and mortality. Recent advancements have elucidated various signaling pathways and therapeutic strategies targeting myocardial fibrosis following MI. This review summarizes key pathways, including TGF-β1, PI3K/AKT, STAT3, AMPK, Nrf2, NF-κB, NLRP3 inflammasome, Wnt/b-catenin, MAPK, and P53, highlighting their potential in therapeutic interventions in recent years. Drug therapy, protein therapy, gene therapy, physical therapy, cell therapy, and exercise training have all shown promise in mitigating fibrosis through these pathways. Notably, multi-pathway therapeutic strategies offer a comprehensive approach to managing myocardial fibrosis, with the TGF-β1 pathway acting as a central hub in the regulatory network. This review underscores the need for further clinical studies to optimize therapeutic strategies and improve outcomes for patients with myocardial fibrosis following MI.
Keywords: Fibrosis, Myocardial Infarction, Therapeutics, Humans, Signal Transduction, Myocardium, Animals, Transforming Growth Factor beta1
Introduction
Myocardial infarction (MI) represents a leading cause of myocardial fibrosis, which contributes to morbidity and mortality from heart disease. The cardiac repair process following MI can be delineated into 3 sequential phases: the inflammatory phase (the first 3 days), the proliferative phase (3–14 days), and the maturation phase (2 weeks-2 months). During the proliferative phase, the extracellular matrix produced by cardiac fibroblasts plays a crucial role in repairing the infarcted area. However, aberrant accumulation of extracellular matrix can give rise to fibrosis, and many signaling pathways are involved in this process [1,2]. Over the past few years, researchers have achieved significant progress in understanding the signaling pathways related to myocardial fibrosis after MI and developing therapeutic strategies that target these pathways. In this review, we examine 10 major signaling pathways involved in myocardial fibrosis following MI, aiming to provide references for further exploration.
TGF-β1
Transforming growth factor-β1 (TGF-β1) stimulates phosphorylation of the downstream Smads protein and translocation of Smads into the nucleus. This induces myocardial fibroblast proliferation, myofibroblast transformation, and collagen expression. These myofibroblasts build extracellular matrix for cardiac repair, but this process can extend to fibrosis [3,4]. Drug therapies that alleviate myocardial fibrosis after MI by inhibiting the TGF-β1/Smads pathway include sacubitril/valsartan [3], empagliflozin [4], curcumin [5], caffeic acid [6], ethyl ferulate [7], icariin [8], calycosin [9], zerumbone [10], retinoid X receptor agonists [11], and the traditional medications nutmeg-5 [12], Guanxin V [13] and Dengzhan Shengmai capsule [14]. Protein therapies such as apelin [15], bone morphogenetic protein 1.3 (BMP1.3) [16], caveolin-1 protein (CAV1) [17], and ectonucleoside triphosphate diphosphohydrolase-1 (CD39) [18] also alleviate myocardial fibrosis following MI by inhibiting the TGF-β1/Smads pathway. As for gene therapies, long-chain noncoding RNA (lncRNA) myosin heavy-chain associated RNA transcript (MHRT) [19] promotes myocardial fibrosis following MI while microRNA-130a has an inhibitory effect [20]. Furthermore, exercise training alleviates fibrosis in mice with MI through inactivating the TGF-β1 pathway [21].
PI3K/AKT
Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) is an important intracellular signaling pathway, and recent studies have confirmed its beneficial therapeutic results on fibrosis following MI. The downstream molecules of the PI3K/AKT pathway include glycogen synthase kinase 3β (GSK-3β), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), endothelial nitric oxide synthase (eNOS), and forkhead box subfamily O (FOXO) [22]. MiR-199a-5p promotes the progression of myocardial fibrosis after MI through the PI3K/AKT/GSK-3β pathway, which provides a gene target for therapy [23]. The drug therapies liriodendrin [24], and emodin [25] ameliorate myocardial fibrosis by inactivating the PI3K/AKT/mTOR pathway. Moreover, traditional medicine Panax Quinquefolium Saponins (PQS) curtails myocardial fibrosis in rats with MI by the PI3K/AKT/eNOS signaling pathway [26]. What’s more, as an upstream element of the PI3K/AKT signaling pathway, phosphatase and tensin homolog (PTEN) functions in anti-fibrosis after MI via the PTEN/PI3K/AKT pathway. Therapeutic strategies targeting PTEN have been mainly based on microRNA in recent years, such as miR-22 [27].
STAT3
Among the signal transducer and activator of transcription (STAT) family, STAT3 plays a key role in promoting cardiac fibrosis, which can be triggered by the Janus kinase (JAK) family [28]. Several different therapeutic strategies aim to attenuate myocardial fibrosis via the JAK/STAT3 signaling pathway. These include drug therapies such as hyperoside [29] and traditional medicine herbal formulas [30], and protein therapies, including nephronectin [31], proprotein convertase subtilisin/kexin type 9 (PCSK9) [32], depletion of Pentraxin 3 (PTX3 KD) [33], and exercise [34]. In addition, gene therapy using circular RNA Whsc1 alleviates cardiac fibrosis by activating the TRIM59 (Tripartite motif family protein 59)/STAT3/Cyclin B2 pathway [35].
AMPK
AMP-activated protein kinase (AMPK) is important for cellular energy homeostasis and plays a protective role in MI damage, in cooperation with various downstream factors [36,37]. The drug therapies capable of inhibiting myocardial fibrosis after MI, as identified in recent studies, include isoliquiritigenin [38], docosahexaenoic acid (DHA) [39], empagliflozin [40], and styrax (Liquidambar orientalis Mill.) [41]. Protein therapies include overexpression of hypoxia inducible factor-1α (HIF-1α) [42] and klotho (an anti-aging protein) [43]. What’s more, exercise reduces cardiac fibrosis in MI rats [44].
Nrf2
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor and plays a crucial role in heart remodeling after MI. Drug therapies comprise the main therapeutic strategies in recent studies. Several of these ameliorate post-MI myocardial fibrosis by regulating the Nrf2 pathway; for example, fucoxanthin [45], ghrelin [46], dietary capsaicin [47], urolithin A [48], tetrahydrocurcumin [49], protocatechuic acid [50], and aloin [51]. What’s more, 2 protein therapies, pan protein arginine deiminase BB-Cl-amidine [52] and activation of steroid receptor coactivator (SRC) [53], as well as gene therapy immune responsive gene 1 (IRG1) [54], inhibit fibrosis via the Nrf2 pathway.
NF-κB
A classical pro-inflammatory signaling pathway, nuclear factor kappa B (NF-κB) is the most common therapeutic target for preventing myocardial fibrosis following MI, among recent studies. Drug therapies such as tubuloside A [55] and the traditional medicine Chaihujialonggumuli granule [56] ameliorate cardiac fibrosis through the NF-κB signaling pathway. Protein therapies such as induced deficiency of Tripartite motif-containing protein 21 (TRIM21) [57] and Nur77 [58]; knockout of ubiquitin-specific protease 38 (USP38) [59], loss of α7 nicotinic acetylcholine receptor (α7nAChR) [60], and suppression of lysosomal-associated protein transmembrane 5 (LAPTM5) [61] attenuate myocardial fibrosis via the NF-κB pathway. Gene therapies such as inhibition of miR-218-5p [62] and mesenchymal stem cell-derived extracellular vesicle-shuttled (MSCs-EVs carrying) microRNA-302d-3p [63] ameliorate myocardial fibrosis through the NF-κB signaling pathway. Cell therapy using atorvastatin-induced tolerogenic dendritic cells (tDC) [64] also reduces myocardial fibrosis through the NF-κB pathway.
NLRP3 Inflammasome
The nucleotide-binding domain, leucine-rich-repeat family, pyrin domain-containing 3 (NLRP3) inflammasome mediates the inflammatory response to MI [22], which is the prephase of myocardial fibrosis as discussed above. To inhibit myocardial fibrosis after MI via NLRP3, traditional medicines and their ingredients constitute the vast majority of drug therapies. These include tradition medicines such as Xin-Li formula [65] and QishenYiqi dripping pill [66], and ingredients such as phloretin [67], bufalin [68], punicalagin [69], muscone [70], and celastrol [71]. Regarding protein therapies and targets, macrophage colony-stimulating factor (M-CSF) [72], ATP responsive P2 purinergic receptors P2X3 antagonist (gefapixant) [73], and myeloid-specific deletion of Capns1 (the common regulatory subunit of calpain-1 and 2)[74] inhibit myocardial fibrosis. Physical therapies such as hydrogen gas inhalation [75] and therapeutic hypothermia [76] ameliorate cardiac fibrosis by regulating the NLRP3 inflammasome in rats with MI.
Wnt/β-Catenin
The term ‘Wnt’ comes from a combination of ‘Wingless’ and ‘Int1’- the same gene discovered at different times [77]. Wnt/β-catenin signaling takes part in promoting cardiac fibrosis following MI by promoting cardiac myofibroblast transformation, collagen production, and capillary proliferation, which suggests potential therapeutic strategies [78,79]. The drug therapies Lcz696 (Sacubitril/Valsartan) [78], XAV939 (a Wnt/β-catenin signaling pathway blocker) [79], and the tradition medicine Linggui Zhugan Decoction [80] delay myocardial fibrosis by inhibiting the Wnt/β-catenin pathway. In addition, recent studies have shown that GSK-3β is a key regulatory factor in the Wnt/β-catenin signaling pathway. Strategies such as miR-145 [81] and the inhibition of tartrate-resistant acid phosphatase 5 (ACP5) can prevent cardiac fibrosis after MI through the pathway of GSK-3β/β-catenin [82].
MAPK
Mitogen-activated protein kinase (MAPK) is capable of responding to a variety of extracellular signals and thus can regulate a wide range of biological effects [83]. The 3 primary branches p38, ERK, and c-Jun N-terminal kinase (JNK) are all related to myocardial fibrosis following MI and cross-linked with each other, and as such are all targets in therapeutic studies. The therapeutic strategies mainly feature protein therapies, such as OTUD7B (Cezanne, a multifunctional deubiquitylate) [84], C1q/tumor necrosis factor-related protein 12 (CTRP12) [85], knockdown of erythropoietin hepatocellular receptor B2 (EPHB2) [86], knockdown of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) [87], downregulation of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) [88], and overexpression of zinc-finger protein 418 (ZNF418) [89]. All of these protein therapies relieve myocardial fibrosis after MI. Drug therapies such us astragaloside IV [90], and peiminine [91], and traditional medicines such as optimized new Shengmai powder [92] and Anshen Shumai Decoction [93], also ameliorate myocardial fibrosis by inhibition of the MAPK signaling pathway.
P53
As a typical suppressor of cancer cell proliferation, P53 can also inhibit the progression of myocardial fibrosis by inhibiting fibroblast proliferation [94]. Drug therapies such as storax [95] and astragaloside IV [96], and protein therapies such as induced deficiency of leucine-rich repeat kinase 2 (LRRK2) [97] and deletion of apoptosis stimulating protein of p53 protein 1 (ASPP1) [94] all alleviate myocardial fibrosis via the p53 pathway. Gene therapy exosomal miR-218-5p/miR-363-3p from endothelial progenitor cells ameliorates MI by targeting the p53 signaling pathway [98]. In addition, there are therapeutic strategies that combine the P53 pathway with other pathways, which will be listed in the multi-pathways section.
Therapeutic Strategies Through Multi-Pathways
There are also quite a number of therapeutic strategies that regulate myocardial fibrosis after MI through multi-pathways. C-C motif chemokine 2 (CCL2)[99], and a dual-specificity phosphatase 6 (DUSP6) inhibitor [100] improve cardiac function and fibrosis in MI rats via regulating the MAPK pathway and the NF-κB pathway. Jatrorrhizine [101], and the long noncoding RNA lncPostn [102] attenuate cardiac fibrosis induced by MI through deactivating the TGF-β1 pathway and activating the P53 pathway. The inflammatory factors S100a8/a9 [103] and A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8) [104] exert their effects through the MAPK and PI3/AKT signaling pathways. Regulators of G protein signaling (RGS) 4 [105] and miR-19 [106] regulate cardiac fibrosis through the TGF-β1 and MAPK signaling pathways. Silencing the dedicator of cytokinesis 2 (DOCK2) gene attenuates cardiac fibrosis after MI via the Wnt/β-catenin and PI3K/AKT pathways [107]. Loganin inhibits angiotensin II-induced cardiac hypertrophy through the JAK2/STAT3 and NF-κB signaling pathways [108]. Ginsenoside F2 ameliorates fibrosis of myocardial tissues by activating the Nrf2/HO-1 and PI3K/AKT signaling pathways [109]. The drug therapies colchicine-containing nanoparticles (ColCaNPs)[110], Diannexin [111], and the traditional medicines LuQi formula [112] and Buyang Huanwu Decoction [113] all work via the NF-κB/NLRP3 signaling pathway. The drug therapy resveratrol [114] works via the AMPK/NLRP3 pathway. The protein therapy inhibition of Sema4D (CD100) works via the MAPK/NF-κB/NLRP3 pathway [115]. In addition, sacubitril/valsartan (Lcz696) alleviates myocardial fibrosis through the TGF-β1 pathway [3] and the Wnt/β-catenin pathway [78]. Empagliflozin works through the TGF-β1 [4] and AMPK pathways [40]. Astragaloside IV works via the MAPK [90] and P53 [96] pathways. Finally, exercise suppresses myocardial fibrosis following MI via activating the TGF-β1 [21], STAT3 [34], AMPK [44], and NLRP3 pathways [116].
Conclusions
Due to the complexity of mechanisms underlying myocardial fibrosis following MI, we have only focused on recent studies. These studies present not only drug therapy and traditional medicine therapy, but also physical therapy and exercise training. It is remarkable that a number of therapeutic strategies in this review function through multi-pathways. As shown in Figure 1, which depicts the fundamental signaling pathways in this review that have associations or “relationships”, we can see that TGF-β1 appears to function as a hub. These depicted pathways form a network modulating myocardial fibrosis following MI. Understanding this network could bring about novel therapies mediated by multi-pathways or combinations of therapeutic strategies from different pathways, improving therapeutic outcome. However, as is shown in Table 1, most strategies are in the animal trial stage. Exceptions include several treatments that exert their effects through multi-pathways and already have clinic trials underway (Table 2), such as sacubitril/valsartan (MAPK+PI3K/AKT), empagliflozin (TGF-β1+AMPK), and exercise training (TGF-β1+STAT3+AMPK+NLRP3). Further studies are needed on clinical applications of each therapeutic strategy; matching specific or multiple pathways with their proper conditions. This approach could lead to more effective treatments. Our review of recent information will contribute to the exploration and application of myocardial fibrosis following MI.
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Tables
Table 1. Preclinical evidence for different therapeutic approaches in post-MI fibrosis.
Table 2. Registered clinical evidence for therapeutic approaches in post-MI fibrosis.Table 1. Preclinical evidence for different therapeutic approaches in post-MI fibrosis.Table 2. Registered clinical evidence for therapeutic approaches in post-MI fibrosis. In Press
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