Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, accounting for more than one-third of global deaths (1, 2). With population aging and the increasing prevalence of cardiometabolic disorders such as hypertension, diabetes, obesity, and chronic kidney disease, the burden of structural heart disease continues to increase. Across diverse etiologies, myocardial fibrosis (MF) has emerged as a common and pivotal pathological substrate underlying adverse cardiac remodeling (3, 4).

Epidemiological studies indicate that myocardial fibrosis is highly prevalent among patients with cardiometabolic diseases and heart failure, affecting approximately one-third of these populations (4), with an even higher prevalence in individuals with long-standing hypertension, ischemic heart disease, or diabetic cardiomyopathy. Importantly, MF is not merely a histopathological finding but is strongly associated with diastolic dysfunction, ventricular arrhythmias, sudden cardiac death, and progression to heart failure (HF) with both preserved and reduced ejection fraction (3).

Advances in noninvasive imaging modalities (5–7), including cardiac magnetic resonance–derived late gadolinium enhancement and extracellular volume quantification, as well as emerging circulating biomarkers (8), have enabled earlier detection and risk stratification of myocardial fibrosis. However, despite advances in diagnosis and risk stratification, effective therapies that directly and specifically target fibrotic remodeling remain limited. Current guideline-directed medical therapies for heart failure, such as renin–angiotensin–aldosterone system (RAAS) inhibitors (9) and sodium–glucose cotransporter 2 (SGLT2) inhibitors (10), exert indirect antifibrotic effects. However, their target specificity is low, and their long-term capacity to reverse established fibrosis is uncertain.

At the mechanistic level, myocardial fibrosis results from the coordinated activation of multiple profibrotic pathways, including mechanical stress–induced signaling, neurohumoral activation, metabolic dysregulation (11), inflammation (12), oxidative stress (OS) (13, 14), and extracellular matrix (ECM) remodeling, ultimately converging on cardiac fibroblast activation and myofibroblast differentiation. A major challenge in the field is the pronounced heterogeneity of fibrotic responses across disease contexts, stages, and myocardial regions, which complicates target identification and therapeutic translation.

Together, these observations highlight the need for a comprehensive and mechanistically grounded understanding of myocardial fibrosis to inform therapeutic development. In this review, we synthesize current evidence on the molecular mechanisms underlying myocardial fibrosis and critically evaluate existing and emerging therapeutic strategies, with a focus on translational relevance and future research directions.

Myocardial fibrosis is driven by a complex and highly interconnected network of molecular mechanisms involving mechanical stress–induced signaling, neurohumoral activation, metabolic dysregulation, inflammatory pathways, oxidative stress, non-coding RNA regulation, and extracellular matrix remodeling. Although these mechanisms are often described as discrete profibrotic axes, they do not operate in isolation. Instead, they interact and converge to regulate cardiac fibroblast activation, myofibroblast differentiation, and excessive ECM deposition, ultimately leading to increased myocardial stiffness and impaired cardiac function.

Importantly, the activation and functional impact of these profibrotic pathways are not uniform but vary according to disease context, stage of injury, and myocardial microenvironment. Recent advances in single-cell RNA sequencing (15) and spatial transcriptomics (16) have provided a conceptual framework for understanding this heterogeneity by revealing that fibrotic signaling pathways are engaged in a cell-state and spatially restricted manner, rather than being uniformly activated across the myocardium. These insights help explain the variable phenotypic manifestations of myocardial fibrosis and the inconsistent therapeutic responses observed in clinical practice.

Within this framework, the following sections outline the major molecular mechanisms underlying myocardial fibrosis, with emphasis on their interactions, regulatory features, and implications for antifibrotic therapy (Figure 1).

This schematic illustrates the interconnected molecular pathways that collectively drive myocardial fibrosis. Mechanical stress is sensed by cardiac fibroblasts through integrins and mechanosensitive ion channels, including transient receptor potential vanilloid 4 (TRPV4) and Piezo1, leading to Ca²⁺ influx and activation of focal adhesion kinase (FAK), RHOA, and mitogen-activated protein kinase (MAPK) signaling cascades. Neurohumoral activation, particularly of the renin–angiotensin–aldosterone system (RAAS), promotes fibroblast activation and myofibroblast differentiation primarily through angiotensin II (Ang II)–induced transforming growth factor-β (TGF-β) signaling, involving both canonical Smad-dependent and non-canonical pathways. Metabolic abnormalities, including elevated levels of glucose and free fatty acids (FFAs), contribute to mitochondrial dysfunction and reactive oxygen species (ROS) overproduction, which amplify profibrotic signaling. Inflammatory responses mediated by immune cells (e.g., macrophages and T cells) further enhance fibrosis through the release of cytokines and chemokines that reinforce shared downstream pathways. Oxidative stress acts as a common amplifier of fibrotic signaling by modulating redox-sensitive pathways, while non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, fine-tune profibrotic gene expression at the post-transcriptional level. These convergent signaling networks ultimately disrupt extracellular matrix (ECM) homeostasis by altering the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to excessive collagen deposition, increased myocardial stiffness, and impaired cardiac function. Arrows indicate activation or amplification.

Given that our understanding of myocardial fibrosis (MF) remains incomplete, and our knowledge of the etiology, timing, and mechanistic heterogeneity of fibrosis formation is still insufficient, there are currently no specific anti-MF drugs routinely used in clinical practice. However, some existing heart failure (HF) treatments have shown promising effects on MF. Additionally, certain non-cardiac drugs may have potential antifibrotic therapeutic effects on MF. In recent years, new strategies and drugs targeting profibrotic factors and pathways have been under development (Table 1).

ACEI and ARB exert antifibrotic effects through the RAAS system, and aldosterone receptor antagonists such as spironolactone can reduce collagen synthesis (77, 78). Recent studies have found that the selective pacemaker current inhibitor ivabradine exhibits antifibrotic potential in animal models by inhibiting CF proliferation and activation through the JNK and p38-MAPK pathways (79). Researchers have found in clinical treatment that the combination of carvedilol and ivabradine improves left ventricular diastolic function and survival rate in patients with cirrhosis (80). Loop diuretics, commonly used in heart failure patients, have also been shown to impact myocardial fibrosis in several studies. In a multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, acetazolamide (81), a carbonic anhydrase inhibitor that reduces sodium reabsorption in the proximal renal tubule, was associated with a higher rate of decongestion in acute decompensated heart failure patients (82). Pirfenidone, an oral drug used to treat idiopathic pulmonary fibrosis, may inhibit collagen synthesis in tissues by reducing the expression of profibrotic and pro-inflammatory cytokines (83). There is some evidence indicating that pirfenidone has antifibrotic activity in various animal models of heart disease. Angiotensin receptor neprilysin inhibitors, such as sacubitril/valsartan, reduce fibrosis by lowering the levels of MMP-1 and soluble ST2 tissue inhibitors (84). SGLT2 inhibitors (10), in addition to their hypoglycemic effects, show beneficial effects in reducing cardiovascular death and hospitalization risks in heart failure (HF) patients, regardless of whether they have type 2 diabetes. This benefit is thought to be mediated through a series of cardiac actions, including myocardial fibrosis (85). Statins, in addition to their lipid-lowering properties, have multiple potential mechanisms that may benefit the heart, including reducing inflammation and fibrosis (86). Soluble guanylate cyclase (sGC) has become a novel therapeutic target for HF. Vericiguat directly stimulates sGC activity within cells, thereby reducing cGMP levels and the cGMP-dependent signaling pathway. It has become a recommended drug in the 2023 National Heart Failure Guidelines, and recent studies have confirmed its antifibrotic effects (87). However, existing drugs often have issues such as poor targeting and uncertain long-term efficacy, and the specific mechanisms by which some drugs act in humans still require further investigation.

At present, many potential therapeutic approaches are still in the stages of cell models, animal models, and clinical trials. First, connective tissue growth factor (CTGF) is downstream of the TGF-β1 pathway, and treatment with the human monoclonal antibody pamrevlumab, which inhibits its activity, has been shown to reduce myocardial type I collagen production in experimental models (88). In a phase II, double-blind, placebo-controlled trial, pamrevlumab demonstrated good safety and showed antifibrotic efficacy in patients with idiopathic pulmonary fibrosis (89). However, some preclinical studies have shown that direct inhibition of TGF-β in the context of heart failure (HF) can lead to severe left ventricular (LV) dilation and increased mortality (90), indicating that this direct targeted therapy should be approached with caution. Second, some ncRNAs are emerging as potential therapeutic targets for organ fibrosis. Targeted therapies involving miR-21 and miR-29, among others, have shown therapeutic effects in clinical trial stages (91, 92), but challenges regarding their stability and safety remain. Third, treatment strategies targeting inflammation-related pathways can also reduce myocardial fibrosis. Cardiac fibroblasts respond to pro-inflammatory processes related to interleukins and S100 proteins, thereby reducing the heart's ability to respond to injury (93). A phase IIa trial of the calpain inhibitor BLD-2660 will evaluate changes in interleukins and S100A9 protein levels in patients with idiopathic pulmonary fibrosis. However, due to the dual nature of S100A8/A9 as both an inflammatory mediator and an anti-inflammatory agent (94), further research is needed to determine the effective dosage of targeted therapeutics. Fourth, immunotherapy offers a new approach to addressing fibrotic diseases. In a mouse model of hypertensive heart disease, chimeric antigen receptor (CAR) T cells specifically targeting fibroblast activation protein were able to reach the heart, eliminate activated fibroblasts, and reduce collagen deposition (95, 96). This provides support for immunotherapy in myocardial fibrosis, but further research is needed to identify other potential cell types expressing antigens that specifically target cardiac fibroblasts and to investigate their precise roles and mechanisms.

Myocardial fibrosis represents a central and potentially modifiable process underlying adverse cardiac remodeling across a wide spectrum of cardiovascular diseases. Accumulating evidence highlights cardiac fibroblast activation, profibrotic signaling pathways such as TGF-β, MAPKs, and inflammatory cascades, as well as metabolic and mechanical stress responses, as key drivers of fibrotic progression. Among emerging therapeutic strategies, interventions targeting fibroblast–immune cell communication, extracellular matrix remodeling, and ncRNA–mediated regulation appear particularly promising for translational application.

Despite these advances, several critical challenges hinder the clinical translation of antifibrotic therapies. Myocardial fibrosis is highly heterogeneous with respect to etiology, disease stage, and spatial distribution, limiting the effectiveness of uniform treatment strategies. Moreover, commonly used animal models fail to fully recapitulate the chronic, multifactorial nature of human cardiac fibrosis. The lack of robust, fibrosis-specific biomarkers further complicates patient stratification and therapeutic monitoring. In addition, many profibrotic pathways play essential roles in tissue repair and homeostasis, raising concerns regarding target specificity and off-target effects.

Future research should focus on precision-based approaches to myocardial fibrosis. Single-cell and spatial omics technologies offer unprecedented opportunities to define disease-specific fibroblast subpopulations and intercellular signaling niches. Artificial intelligence–assisted analyses may facilitate target prioritization, drug repurposing, and rational drug design. Finally, combination therapeutic strategies that simultaneously modulate inflammation, metabolism, and extracellular matrix dynamics may provide superior efficacy compared with single-target interventions. Together, these approaches are expected to advance the development of safe and effective antifibrotic therapies and improve outcomes for patients with cardiovascular disease.