ACEIs are one of the most studied and effective drug types in the treatment of MF (Jessup et al., 2009). Blocking the renin angiotensin system (RAS) with ACEIs can prevent fibrosis development (Table 1) (Liu et al., 2021). Perindopril is a powerful and long-lasting ACEI (Li et al., 2019). Recent studies have shown that perindopril can alleviate MF by reducing the levels of galectin-3 (Gal-3) (Figure 2) (Li et al., 2019; Hu et al., 2022; Blanda et al., 2020; Slack et al., 2021). Captopril is a classic drug for the clinical treatment of MF (Yoshimura et al., 1989). It inhibits MF in two ways (Zhang et al., 2019; Plosker and McTavish, 1995; Schalekamp et al., 1980; Akhtar et al., 2022; Rha et al., 2021; Li et al., 2022). First, it can hinder the conversion of angiotensin I to angiotensin II by inhibiting ACE (Zhang et al., 2019; Plosker and McTavish, 1995; Schalekamp et al., 1980). It can improve ventricular remodeling and inhibit the occurrence of MF (Figure 2) (Akhtar et al., 2022). Second, captopril can inhibit MF by downregulating α-smooth muscle actin and vimentin expression (Rha et al., 2021; Li et al., 2022).

MF can result from cardiovascular diseases such as myocardial infarction and atherosclerosis. Although ACEI is the most commonly used antihypertensive drug, it is underutilized in the treatment of heart failure and left ventricular dysfunction after myocardial infarction and its application in treating atherosclerosis is limited (Howes and Christie, 1998; Dendorfer et al., 2005). In addition, the molecular mechanisms through which perindopril can alleviate interstitial collagen deposition in the myocardium and inhibit MF have not been elucidated, which hinders its application in the treatment of MF (Li et al., 2019).

It has been proven that the phenomenon of “aldosterone escape” determines the irreplaceable role of aldosterone antagonists in the treatment of MF (Table 1) (Buffolo et al., 2022; Schimmel et al., 2022; Rossier, 2021). It has been shown that eplerenone’s high affinity for Kv1.3 channels, potassium channel proteins on the T-lymphocyte (Treg) membrane, enables it to antagonize Kv1.3 channels directly to suppress the proliferation of Tregs that can secrete TGF-β (Shao et al., 2018; Chen et al., 2016). Therefore, eplerenone can alleviate MF (Shao et al., 2018; Chen et al., 2016). Canrenoate potassium, a new aldosterone receptor antagonist, has fewer side effects related to sex hormones than spironolactone (Bos et al., 2005). It alleviates isoproterenol-induced MF in rats by inhibiting the RAAS (Bos et al., 2004). The long-acting loop diuretic torsemide can antagonize aldosterone, antagonize the physiological effect of aldosterone on water sodium retention, inhibit the activation of the RAAS (Figure 2), and expel excess water from between tissues, which avoids the side effects of hyperactivity of the RAAS system caused by long-term use of diuretics (Kurlykina et al., 2017; Ghionzoli et al., 2022). Therefore, torsemide has a good cardioprotective effect that delays or reverses MF. In addition, inhibiting aldosterone synthase (CYP11B2) with torsemide prevents atrial fibrosis and atrial fibrillation in mice (Adam et al., 2015).

Diuretics, a type of the most frequently used medications, are well tolerated (Diuretics, 2021). Their common side effects resulting from the diuresis and mineral loss include weakness, dizziness, electrolyte imbalance, low sodium and low potassium (Diuretics, 2021). Aldosterone receptor antagonists have therapeutic effects on MF without increasing aldosterone or inducing sodium retention, but under other physiological conditions, it is unknown whether they also have the same potency (Rossier, 2021). Dose-dependent blood potassium elevation is an adverse reaction of eplerenone (Struthers et al., 2008). In addition, eplerenone is also associated with sexual side effects (Struthers et al., 2008). Torsemide has significant advantages in terms of diuretic effects and high bioavailability (Greene et al., 2021). Previous studies have proven that torsemide can inhibit MF and reverse ventricular remodeling (López et al., 2004; López et al., 2007). However, its detailed mechanisms remain unclear.

β receptor blockers can treat MF and other cardiovascular diseases (Ke et al., 2023). Hyperactivation of the sympathetic nerve is one of the common pathophysiological mechanisms of MF and many cardiovascular diseases (Table 1) (Czuriga and Edes, 2004; Perlini et al., 2005). β receptor blockers can inhibit the effects of epinephrine and norepinephrine on multiple tissues and systems, thereby inhibiting MF (Oliver et al., 2019).

Propranolol is a type of β receptor blocker (Tsai et al., 2022). It can cut off the β2 receptor and inhibit the cyclic adenosine phosphate (CAMP)/protein kinase A (PAK) nitric oxide signaling pathway to alleviate MF (Nuamnaichati et al., 2018). Propranolol inhibits MF by inhibiting the expression of fibroblast growth factor-23 (FGF-23) (Figure 2) (Tsai et al., 2022).

Carvedilol is the most effective way to improve the survival rate after myocardial infarction (Zheng et al., 2019). Carvedilol, a blocker of β1 and β2 adrenergic receptors (ARs), ameliorates MF induced by a high-fructose/high-fat diet in mice by enhancing cardiac β-arrestin 2 signaling (Figure 2) (Ibrahim et al., 2020; Ibrahim et al., 2021).

β receptor blockers are one of the most commonly used drugs and are usually well tolerated (Diuretics, 2018). However, β-adrenergic blockade can lead to common side effects, including bradycardia, fatigue, dizziness, depression, memory loss, insomnia, impotence and chills in the limbs (Diuretics, 2018). The mechanism by which propranolol can compensate for local nitric oxide deficiency in arterial circulation is still unclear, which limits its application (Pacca et al., 2002). Although carvedilol can inhibit MF, its exact mechanism remains unknown (Zhu et al., 2013).

Other modern medicines, such as irisin and clopidogrel, have therapeutic effects on MF (Pan et al., 2021; Jia et al., 2013). Irisin inhibits MF by inhibiting the levels of reactive oxygen species (ROS) and the NF-KB-Snail Signaling Pathway (Pan et al., 2021). Clopidogrel inhibits platelet activation, inhibits platelet leukocyte binding, and causes inflammatory cells to secrete cytokines (IL-1) into the heart, thus inhibiting MF (Table 2) (Jia et al., 2013; Liu et al., 2020).

Compared with single drug treatment of MF, the combined use of different types of drugs to treat MF is superior (Cohn, 2003). After myocardial infarction in rats, the therapeutic effect of the combination of eplerenone and the angiotensin Ⅱ receptor antagonist (ARB) candesartan was better than that of single drug therapy (Fraccarollo et al., 2003). The combination of β receptor blockers and ACEIs can provide a comprehensive neuroendocrine blocking effect, especially in the heart and blood vessels (Demkes et al., 2021).

Modern medicine inhibits MF by downregulating certain signaling pathways (TGF-β/Smad, cAMP-PAK-NO, RAAS), protein levels (factor-23, Gal-3, ACE) and receptors (β2 receptor). Gal-3: galectin-3; RAAS: renin-angiotensin-aldosterone system; Ang Ⅰ: angiotensin Ⅰ; Ang Ⅱ: angiotensin Ⅱ; TGF-β: transforming growth factor-β; β-Arrestin 2: a key protein regulating endothelial nitric oxide synthase activity; CYP11B2: aldosterone synthase; KV1.3: the Kv1.3 channel, a potassium channel protein on the membrane of T lymphocytes; cAMP-PAK-NO: cyclic adenosine phosphate (CAMP)/protein kinase A (PAK) nitric oxide signaling pathway; FGF-23: fibroblast growth factor-23; Smad: a TGF-β intracellular signaling molecules in the cytokine superfamily; α-SMA: α-smooth muscle actin; vimentin: a fibroblast marker; ACE: angiotensin converting enzyme.

Salvia miltiorrhiza and Carthamus tinctorius extracts (SCE) have been widely used in clinical practice and have achieved good effects in the treatment of myocardial ischemia and MF (Table 1) (Wang et al., 2020). The chalcone pigment safflower yellow (SY) is the main effective component of Carthamus tinctorius (Bai et al., 2020). SY can be used to treat atherosclerosis by reducing blood lipid levels and improving antioxidant capacity (Bai et al., 2020). Danshinone, an active component of Salvia miltiorrhiza, can ameliorate MF (Jiang et al., 2019). It has two mechanisms. First, danshinone has been suggested to reverse the increase in the levels of collagen type 1 (Col1), collagen type 3 (Col3) and α-smooth muscle actin (α-SMA) in HF rats induced by ligation of the left anterior descending branch (LAD) of the coronary artery through upregulating miR-205-3p, miR-29b, or miR-618 (Yang et al., 2023). Second, MF is achieved by downregulating the TGF-β/SMAD2/3 signaling pathway (Ren et al., 2022).

A mixture of active ingredients from SCE can exert a synergistic effect (Orgah et al., 2020). This combined medication is better than individual medicines in terms of the therapeutic effects on cardiovascular diseases (Orgah et al., 2020). It was reported that the effect of SCE on attenuating fibrosis was closely linked with the downregulation of TGF-β/Smad3 signaling and that SCE can inhibit the increase in the levels of H3K4me3 and H3k36me3 in the Smad3 promoter region induced by TGF-β in CFs (Figure 3) (Yang et al., 2019). In addition, when the levels of water-soluble effective components (salvianolic acid B and hydroxysafflower yellow A) of SCE are increased, they can protect the damaged heart by inhibiting tissue oxidation, inflammatory cell infiltration and platelet aggregation (Orgah et al., 2020).

The results of experimental research and clinical practice have proven that SCE can exert a good therapeutic effect on MF, but potential targets and molecular mechanisms of its inhibitory effects on MF need to be further studied.

Astragalus is a promising antifibrotic drug (Ren et al., 2023). Its main antifibrotic components are calycosin, astragaloside IV, astragalus polysaccharides and formononetin (Tan et al., 2020) (Table 1). It has been confirmed that astragalus membranaceus and its effective components can inhibit MF (Pan and Zhu, 2018). Astragalus saponins can inhibit the TGF-β/Smad pathway and P38 MAPK/NF-KB pathway, alleviating MF (Figure 3) (Zhu et al., 2022). Astragaloside IV has four mechanisms (Pan et al., 2021; Li et al., 2023; Zhang et al., 2022; Wan et al., 2018; Wei et al., 2020; Li et al., 2021; Lu et al., 2017). First, astragaloside IV inhibits the TGF-β-smad signaling pathway to inhibit MF (Pan et al., 2021; Li et al., 2023). Second, astragaloside IV alleviates MF by suppressing the ROS/caspase1/gasdermin D (GSDMD) signaling pathway in mice (Figure 3) (Zhang et al., 2022). Third, astragaloside IV exerts antifibrotic effects by inhibiting the NOD-like receptor family pyrin domain-containing 3 (NLRP3)/caspase I/IL-18 pathway in mice with isoproterenol-induced cardiac fibrosis (Figure 3) (Wan et al., 2018). Fourth, astragaloside IV significantly downregulates the transient receptor potential melastatin 7 (TRPM7) channel to inhibit hypoxia-induced cardiac fibrosis. Astragaloside IV can alleviate cardiac fibrosis by targeting the mir-135a-TRPM7-TGF-β/Smad pathway (Figure 3) (Wei et al., 2020; Li et al., 2021; Lu et al., 2017).

It has been reported that astragalus membranaceus has therapeutic effects on MF, but its material basis remains unclear (Ren et al., 2023). Moreover, there are many research limitations. Technical limitations suggest that the exact components of astragalus mongholicus Bunge or the compound medicine cannot be fully determined. In addition, the exact therapeutic effect of astragalus mongholicus Bunge on MF cannot be accurately determined by a multicomponent study, and the results of randomized controlled trials demonstrating its efficacy are not sufficient (Ren et al., 2023).

Angelica contains a variety of components that have a wide range of biological activities, such as immune regulation, liver protection, and antiatherosclerotic, antitumor, anti-inflammatory and analgesic activities (Table 1) (Chang et al., 2021).

It has been reported that butylphthalide, the active ingredient of angelica, can activate the P13K/STAT3 pathway by downregulating miR-22, reducing H9c2 cell damage and inhibiting MF during myocardial infarction under hypoxia in vitro (Figure 3) (Lin et al., 2019). Angelica sinensis polysaccharide (ASP), a major bioactive component extracted from the roots of angelica, has antioxidative activity and can treat multiple diseases resulting from oxidative stress (Song et al., 2021). ASP can decrease ROS levels in a dose-dependent manner (Song et al., 2021; Pan and Zhu, 2018). It has been shown that ASP can alleviate cardiac fibrosis by inhibiting oxidative stress (Song et al., 2021; Pan and Zhu, 2018). The underlying and detailed mechanisms by which ASP prevents MF are worthy of further study.

Other TCMs, such as curcumin, earthworms and ginsenoside, have therapeutic effects on MF (Yu et al., 2019; Lai et al., 2015; Wang et al., 2021). Curcumin decreases cardiac fibrogenesis by activating SIRT1, increasing Nrf2, and increasing NADPH oxidase subunits (Sadoughi et al., 2021; Ren et al., 2022). Earthworms can inhibit MF by inhibiting the levels of MF-related proteins in H9c2 cells (Huang et al., 2019). Ginsenoside Re, the active ingredient of ginsenoside, can alleviate MF by inhibiting the miR-489/MyD88/NF-ΚB signaling pathway (Table 2) (Sun et al., 2023).

Traditional Chinese medicine inhibits MF by downregulating some related signaling pathways (P13K/STAT3, TGF-β/Smad, NF-KB), related molecules (miR-22, H3K36, H3K4me3, miR-618), and levels of reactive oxygen species. ROS: reactive oxygen species; NF-kB: K gene binding nuclear factor; TRPM7: transient receptor potential melastatin 7; P38: an important stress activating member of the MAPK family; STAT3: signal transduction and activator of transcription; P13K: phosphoinositide 3 kinase; NLRP3: nucleotide binding oligomerization domain-like receptor protein 3; IL-18: interleukin-18; caspase 1: cysteinyl aspartate specific proteinase 1; Col1: collagen type 1; Col3: collagen type 3; H3K4me3: trimethylation of lysine in the third subunit of histone 4; H3K36me3: histone 3 lysine 36 trimethylation.

Other modern medicine and traditional Chinese medicine inhibit MF through relevant molecular mechanisms (ROS/NF-KB-Snail pathway, ERK1/2, uPA, SP1, CTGF proteins). SIRT1: Silencing regulatory protein 1; Nrf2: encoded by the NFE2L2 gene, regulating approximately 250 genes involving in cellular homeostasis; H9C2 cells: Embryonic rat cardiomyocytes; uPA: a multifunctional serine protease with a relative molecular weight of 55,000 kDa, which can be synthesized by fibroblasts, monocyte, neutrophils, epithelial cells, and tumor cells; SP1: sequence-specific DNA binding proteins that regulates the transcription of cellular and viral genes rich in GC sequences in certain promoters. It is an important and essential transcription factor. CTGF protein: connective tissue growth factor protein.