Cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease: Mechanisms, clinical implications and therapeutic opportunities

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the predominant hepatic manifestation of systemic metabolic dysfunction and an independent risk factor for cardiovascular disease. Recent evidence supports the cardio-hepatic axis as a bidirectional communication network between the liver and the cardiovascular system. In MASLD, the liver releases lipotoxic metabolites, hepatokines, and extracellular vesicles that contribute to endothelial dysfunction, vascular inflammation, atherosclerotic plaque progression, and adverse myocardial remodeling; conversely, cardiac dysfunction promotes liver injury and fibrosis via venous congestion and neurohumoral activation. Systemic inflammation, gut dysbiosis, and genetic susceptibility collectively constitute amplification networks of the cardio-hepatic axis, establishing MASLD as a cardiometabolic disorder. Liver fibrosis severity and cardiovascular risk demonstrate a parallel relationship in MASLD patients. We propose a risk stratification framework integrating liver fibrosis screening into cardiovascular risk assessment. Therapeutically, the approach shifts from single-organ targeting to systemic cardio-hepatic axis modulation, with multiple regimens exerting dual effects on both organs. This review synthesizes current evidence on the mechanisms, risk stratification, and therapeutic approaches of the cardio-hepatic axis in MASLD, providing a conceptual roadmap for cardio-hepatic comorbidity.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Cardio-hepatic axis; Cardiovascular disease; Risk stratification; Therapeutic strategies

Core Tip: Metabolic dysfunction-associated steatotic liver disease is a systemic cardiometabolic disorder driven by the cardio-hepatic axis. This review examines bidirectional signaling and systemic amplification networks within this axis and explores its intrinsic mechanisms. Based on population evidence, we propose a risk stratification framework that integrates metabolic dysfunction-associated steatotic liver disease evaluation into cardiovascular risk assessment, shifting management from a liver-centric to a systemic cardio-hepatic co-management model. We also critically appraise therapeutic strategies targeting these mechanisms according to clinical evidence strength. However, key challenges remain, including the liver-heart causal relationship, the lack of a risk assessment system capturing cardio-hepatic crosstalk, and the limited availability of axis-specific randomized controlled trials.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not confined to the liver; instead, as a systemic metabolic disease, it affects more than 30% of adults worldwide[1-3]. MASLD is associated with an elevated risk of cardiovascular disease (CVD), which increases alongside fibrosis progression[4,5]. Notably, this risk association remains significant even after adjusting for shared metabolic factors including obesity and insulin resistance[6], indicating the presence of a more direct inter-organ connection, which has been defined as the “cardio-hepatic axis”[7]. This concept holds that the liver and the heart maintain direct bidirectional communication.

Several systematic reviews focusing on the cardio-hepatic axis have been published to date[8,9]. However, these existing reviews either exclusively focus on liver-to-heart signaling or exhibit limited clinical applicability. A research gap remains in the stratified risk assessment and evidence-graded therapeutic decision-making for this disease context. Accordingly, we performed a narrative review based on a systematic literature search of PubMed and Web of Science (from database inception to 2026), with supplementary manual screening of reference lists of eligible studies.

This review presents three distinct contributions to the field. First, it critically evaluates the supporting evidence in a narrative format and explores the underlying mechanisms of the cardio-hepatic axis based on preclinical and exploratory research findings. Second, it constructs a risk stratification framework to guide the management of MASLD patients at increased risk of adverse hepatic and cardiovascular outcomes. Third, it synthesizes the evidence levels of pharmacotherapeutic strategies targeting the core underlying mechanisms, thereby providing a basis for drug selection. This review also systematically identifies and discusses current evidence gaps and unresolved questions, which differentiates it from previously published reviews.

BIDIRECTIONAL MECHANISMS OF THE CARDIO-HEPATIC AXIS IN MASLD

MASLD interacts with the cardiovascular system via a bidirectional cardio-hepatic axis. The liver transmits pathogenic signals to the heart through lipotoxic metabolites, hepatokines, and extracellular vesicles (EVs), whereas cardiac dysfunction exacerbates liver injury via hemodynamic alterations, neurohumoral activation, and cardiogenic endocrine signaling. Importantly, the crosstalk between the heart and liver is not limited to these two organs. Multiple additional factors, including immunometabolism, gut-derived signals, circadian rhythms, as well as genetic and epigenetic modifications, can further amplify this inter-organ crosstalk. Collectively, these factors drive the progression of MASLD from a localized liver disease to a systemic cardiometabolic disease. The potential mechanisms underlying the cardio-hepatic axis are elaborated from three key perspectives below (Figure 1).

Figure 1 Schematic diagram of bidirectional crosstalk and systemic regulatory networks in the cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease. The central white circle illustrates the direct bidirectional dialogue between the liver and the heart: The liver acts on the heart through extracellular vesicles, while the heart reciprocally regulates the liver through the secretion of atrial natriuretic peptide and B-type natriuretic peptide, accompanied by target organ phenotypes. The grey annular band encircling the core region summarizes the pathogenic mediators intertwined with the systemic amplification networks that drive shared core pathways underlying concurrent cardiac and hepatic injury. The outermost four modules, immunometabolic network, gut signaling network, circadian rhythm network, and genetic/epigenetic/CHIP, further exacerbate the vicious cycle of the cardio-hepatic axis by amplifying pathological molecular levels within the loop. For a detailed list of all specific molecules mediating these interactions, see Table 1. PCSK9: Proprotein convertase subtilisin/kexin type 9; FXI: Factor XI; FGF21: Fibroblast growth factor 21; ANGPTL3: Angiopoietin-like protein 3; SAA1/4: Serum amyloid A1/A4; EVs: Extracellular vesicles; ANP: Atrial natriuretic peptide; BNP: B-type natriuretic peptide; HSC: Hepatic stellate cell; MASH: Metabolic-dysfunction-associated steatohepatitis; AngII: Angiotensin II; GDF15: Growth differentiation factor 15; CHIP: Clonal hematopoiesis of indeterminate potential.

Liver-to-heart crosstalk

Lipotoxicity and metabolic signaling: Lipotoxicity is tightly linked to MASLD-related cardiovascular complications. Under conditions of obesity and insulin resistance, enhanced hepatic fatty acid uptake and synthesis lead to excessive accumulation of toxic lipids in hepatocytes. This process induces cellular stress and cell death, and has been verified to facilitate the progression of hepatic inflammation and fibrosis in animal models[10]. Once the liver’s lipid storage capacity is exceeded, lipotoxic metabolites spill over into the circulation, imposing an abnormal lipid burden on the heart.

Hepatocyte-specific peroxisome proliferator-activated receptor alpha (PPARα) knockout mice exhibit increased cardiac triglyceride content, reduced myocardial contractility, and enhanced collagen deposition in the absence of obesity[11]. In Western diet-induced metabolic dysfunction-associated steatohepatitis (MASH) mice, elevated hepatic ceramide synthesis correlates with increased sphingolipid concentrations in both plasma and cardiac tissue[12]. In mice with hepatic mitochondrial dysfunction, steatosis drives the remodeling of circulating lipoproteins and alterations in the cardiac lipidome. Diastolic dysfunction can be specifically observed in male mice[13]. As indicated by in vitro studies, lipotoxic metabolites can activate the stimulator of interferon genes pathway and induce cardiomyocyte ferroptosis[14]. Furthermore, lipid metabolic reprogramming may contribute to cardiac fibrosis via multiple pathways[15].

In brief, evidence from animal and cellular studies supports the association between hepatic lipotoxicity and cardiac injury in the context of MASLD. Existing evidence remains predominantly preclinical. Whether lipotoxic metabolites directly trigger myocardial injury in humans, as well as the magnitude of their causal contribution, lacks validation from large-scale prospective cohort studies and requires further systematic investigation.

Hepatokines: As a vital endocrine organ, the liver undergoes substantial changes in secretory profiles, which are recognized as a core mechanism mediating liver-heart crosstalk. In the setting of MASLD, the liver secretes a spectrum of signaling molecules that modulate cardiac structure and function through endocrine pathways. Fibroblast growth factor 21 (FGF21) is a liver-derived metabolic regulator. It exerts dual effects on the heart. Animal studies have demonstrated that FGF21 suppresses hepatic de novo lipogenesis and reverses fibrosis via the central nervous system. It can while simultaneously reduce cholesterol through direct actions on hepatocytes, thereby synergistically reversing MASH through a dual mechanism[16]. In a heart failure with preserved ejection fraction (HFpEF) animal model, FGF21 was found to improve myocardial mitochondrial bioenergetics via the adiponectin-PI3K/protein kinase B-PDK4 signaling pathway[17]. Based on these preclinical observations, clinical trials have confirmed that FGF21 analogs improve serum lipid profiles and MASH fibrosis[18]. A population-based observational study of high-risk patients with coronary heart disease from the TNT trial demonstrated that elevated circulating FGF21 levels are independently correlated with an increased risk of major cardiovascular events[19]. As revealed by the above-mentioned paradox, elevated endogenous FGF21 is a compensatory response to metabolic stress, whereas the compensation may be insufficient to arrest disease progression. The clinical translation of FGF21 is subjected to multiple barriers, encompassing its short half-life and suboptimal efficacy across different settings. It is necessary to investigate whether the cardioprotective effects of exogenous FGF21 can be replicated in human populations.

Coagulation factor XI (FXI) is predominantly synthesized by the liver. Elevated FXI activity has been detected in patients with MASLD and shows a positive correlation with hepatic fat content[20]. FXI exerts two distinct biological effects on the cardiovascular system. A population-based meta-analysis has demonstrated that circulating FXI levels are positively associated with the risk of cardiovascular events in the general population[21]. Nevertheless, existing evidence from an HFpEF animal model indicates that FXI confers a protective effect on cardiac diastolic function via its proteolytic activity. Specifically, FXI cleaves the extracellular matrix-bound BMP7 precursor in the heart, thereby activating the myocardial BMP-SMAD1/5 signaling pathway and inhibiting the expression of inflammatory and fibrotic genes[22]. Consistent with these animal experimental findings, population-based cohort studies have confirmed that reduced FXI levels are correlated with elevated heart failure risk and aggravated diastolic dysfunction[23]. Collectively, these findings indicate that FXI promotes thrombotic risk in the circulatory system through procoagulant pathways, whereas it mediates distinct local cardiac effects via non-coagulant pathways.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized in the liver and subsequently secreted into the bloodstream. Population-based genetic studies have verified that loss-of-function variants of the PCSK9 gene are associated with markedly decreased low-density lipoprotein cholesterol (LDL-C) levels and a reduced risk of coronary heart disease[24,25]. Animal studies have further suggested that PCSK9 may directly regulate vascular wall inflammation, with such effects potentially independent of its LDL-C-lowering function[26]. Moreover, animal models with complete PCSK9 deficiency exhibit typical HFpEF-like phenotypic alterations, including impaired cardiac mitochondrial respiratory function, increased cardiac lipid deposition, and left ventricular wall thickening[27]. However, human translational evidence remains inconsistent with these animal observations. A genetic study enrolling 35135 participants from the UK Biobank found no significant association between PCSK9 loss-of-function variants and left ventricular mass, cardiac function, or heart failure[28]. These results suggest that the local cardiac effects of PCSK9 may be species-dependent, and its exact pathophysiological role requires further investigation.

Angiopoietin-like protein 3 (ANGPTL3) is mainly produced by the liver. It functions to inhibit lipoprotein lipase and endothelial lipase, which impairs the clearance of triglyceride-rich lipoproteins and LDL-C, and consequently elevates circulating lipoprotein levels. In animal studies, antisense oligonucleotide-mediated knockdown of hepatic ANGPTL3 mRNA in mice reduced hepatic triglyceride accumulation and improved systemic insulin sensitivity[29]. Existing lipidomics data also imply a potential association between ANGPTL3 and the phosphatidylinositol pathway; however, this correlation remains preliminary, and the specific underlying molecular mechanisms have not been fully elucidated[30].

Serum amyloid A (SAA) is a liver-derived acute-phase protein that has attracted increasing research attention in the context of chronic metabolic disorders, including MASLD[31]. A recent systems biology study integrated liver and cardiac transcriptomic data from a mouse HFpEF model, as well as human HFpEF plasma proteomic data and MASLD multi-omics data, and identified SAA1 and SAA4 as key candidate mediators of liver-heart crosstalk. These two molecules represent an obesity-independent and HFpEF-specific molecular signal[32]. In vitro and animal studies have further shown that SAA1 may activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase inflammatory pathways and the transforming growth factor-beta (TGF-β)/Smad pro-fibrotic pathway, thereby promoting cardiac fibrosis[33]. As revealed by the above-mentioned findings, SAA may function as a liver-derived pro-fibrotic effector molecule involved in liver-heart crosstalk; however, its pathogenic role in humans requires further validation.

EV-mediated signaling: EVs are nanoscale vesicles secreted by cells that carry bioactive molecules including proteins, lipids, and nucleic acids, and participate in inter-organ communication under both physiological and pathological conditions[34]. Accumulating animal and cellular studies have demonstrated that EVs derived from steatotic hepatocytes promote vascular inflammation and atherosclerosis via delivering microRNA-1 (miR-1), which suppresses endothelial Krüppel-like factor 4 expression and activates the NF-κB signaling pathway[35]. Moreover, EVs released by steatotic hepatocytes are highly enriched in miR-30b-5p, which may inhibit polyunsaturated fatty acid synthesis by targeting ELOVL5 (a member of the ELOVL fatty acid elongase family), and this mechanism is closely linked to endothelial inflammation and atherosclerosis progression[36]. EVs can also mediate protective biological signals, and their functional properties appear to be dependent on the metabolic status of the liver. In early-stage obese mice, hepatocyte-derived exosomes with high miR-3075 abundance have been reported to improve insulin sensitivity in adipocytes, myocytes and hepatocytes by targeting fatty acid 2-hydroxylase. In contrast, this protective effect is abolished under chronic obese conditions, and hepatocyte-derived exosomes alternatively facilitate insulin resistance by inducing inflammatory polarization of macrophages[37]. These findings indicate that EVs exert dual pathogenic and protective effects in the cardio-hepatic axis. Nevertheless, existing evidence is predominantly obtained from preclinical studies, and their exact physiological and pathological implications in humans remain to be further elucidated.

Heart-to-liver feedback regulation

Cardiac dysfunction can affect hepatic function through three major pathways, namely hemodynamic abnormalities, neurohumoral activation, and cardiogenic endocrine signals, thereby forming a bidirectional closed-loop regulatory network of the cardio-hepatic axis.

Hemodynamic abnormalities: The liver is highly susceptible to systemic hemodynamic fluctuations, and venous congestion secondary to cardiac dysfunction is a key contributor to hepatic structural and functional damage. Clinical investigations have revealed that over two-thirds of HFpEF patients present with abnormally elevated liver stiffness, which is significantly correlated with deteriorated left ventricular diastolic function, aggravated left ventricular hypertrophy, and impaired right ventricular function. Notably, HFpEF patients complicated with right ventricular dysfunction exhibit higher liver stiffness levels, and liver stiffness has been validated as an independent prognostic biomarker for short-term clinical outcomes in HFpEF patients[38]. Multicenter clinical studies have further verified that liver stiffness values are significantly positively correlated with invasively measured central venous pressure[39]. These clinical observations indicate that heart failure-induced hemodynamic disturbances (elevated central venous pressure) are closely associated with hepatic injury. Relevant animal studies have further clarified the underlying molecular mechanisms. In a murine chronic hepatic congestion model established via partial inferior vena cava ligation, significant hepatic stellate cell activation, marked hepatic fibrosis accumulation, and increased portal pressure were observed. Mechanistically, venous congestion activates hepatic stellate cells through two distinct pathways, including hepatic sinusoidal thrombosis and mechanical stretch stimulation[40]. In vitro experiments further confirm that mechanical stretch directly upregulates MMP1 production and increases the MMP1/TIMP1 ratio in human hepatic stellate cells, demonstrating that mechanical force alone is sufficient to disrupt the matrix metabolic balance of hepatic stellate cells[41].

Neurohumoral and endocrine signaling: Activation of the renin-angiotensin-aldosterone system (RAAS) associated with reduced cardiac output serves as a potential neurohumoral mechanism. It bridges cardiac dysfunction and hepatic pathology. Angiotensin II (AngII) acts as the core effector molecule of the RAAS. As indicated by in vitro studies, activated human hepatic stellate cells express the AngII type 1 receptor. Through this receptor, AngII elevates intracellular calcium concentration to trigger cell contraction, while simultaneously promoting DNA synthesis and cell proliferation[42]. Mechanistically, in vitro observations indicate that AngII induces the nicotinamide adenine dinucleotide phosphate oxidase regulatory subunit p47phox to generate reactive oxygen species. This process further activates the phosphorylation of AKT and MAPKs, enhances activator protein-1 DNA binding activity, and facilitates DNA synthesis, cell migration, type I procollagen mRNA expression, as well as the secretion of TGF-β1 and inflammatory cytokines in hepatic stellate cells[43]. Accumulated evidence also reveals that AngII upregulates the mRNA expression of all three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3) in both quiescent and activated hepatic stellate cells via the extracellular signal-regulated kinase 1/2 and nicotinamide adenine dinucleotide phosphate oxidase pathways, thereby promoting the production of active TGF-β protein[44]. Notably, these findings are primarily obtained from in vitro cellular experiments. The complete signaling network of AngII in human hepatic stellate cells and its in vivo pathophysiological significance remain to be fully elucidated.

Furthermore, the sympathetic nervous system participates in the regulation of hepatic metabolism. Animal studies have demonstrated that intrahepatic sympathetic innervation density decreases markedly during MASLD progression, which exacerbates disease progression by modulating hepatic blood perfusion, lipid metabolism, and inflammatory responses[45]. Sympathetic nervous system activation is a common characteristic of heart failure, and such activation may further alter hepatic function via hepatic nerve pathways. Nevertheless, the specific role of the sympathetic nervous system in MASLD and its interactive association with heart failure are still under investigation and require further systematic exploration.

Cardiogenic endocrine signals: The heart communicates with systemic organs via the secretion of multiple hormones[46]. Under cardiac dysfunction conditions, these cardiogenic signals can modulate the metabolic and inflammatory phenotypes of the liver. Animal studies have verified that cardiac-secreted atrial natriuretic peptide (ANP) and B-type natriuretic peptide induce the “browning” of white adipocytes through the p38 MAPK pathway, which increases whole-body energy expenditure and thermogenesis[47]. It is hypothesized that the heart indirectly regulates hepatic metabolic function by modulating systemic energy metabolism, though direct experimental evidence supporting this hypothesis is currently lacking.

Growth differentiation factor 15 (GDF15) is a crucial cardiogenic factor whose expression is significantly upregulated in heart failure. Animal studies have shown that GDF15 activates β-adrenergic signaling through the GDNF family receptor alpha-like receptor, thereby improving insulin sensitivity in the liver and adipose tissue independent of body weight changes[48]. Additionally, GDF15 can alleviate hepatic fibrosis by inducing metabolic reprogramming of macrophages[49]. However, these conclusions are predominantly based on preclinical research, and their biological implications in human subjects require further validation.

Systemic amplification network of the cardio-hepatic axis

The bidirectional communication between the liver and the heart does not occur in complete isolation. However, it is likely to be involved in a multisystem regulatory network that encompasses immunometabolism, gut-derived signals, circadian rhythms, and genetic or epigenetic factors. The above-mentioned pathways may interact through shared mediators (e.g., inflammatory signals). They mutually reinforce each other and expanding the cardio-hepatic axis from local inter-organ crosstalk to a systemic metabolic network.

Immunometabolic network: At the local hepatic level, the accumulation of free fatty acids can induce mitochondrial dysfunction, generating lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns, together with gut-derived pathogen-associated molecular patterns, activate Kupffer cells and the innate immune system[50]. At the mechanistic level, elevated β-arrestin 2 expression has been observed in hepatic macrophages from patients with MASH; this elevation may inhibit itaconate production by promoting immune-responsive gene 1 ubiquitination and is associated with M1 macrophage polarization[51]. Periportal thyroid hormone-responsive spot 14 protein+ hepatocytes have been shown to recruit CD74+ lipid-associated macrophages via macrophage migration inhibitory factor, forming hepatocyte-macrophage crosstalk[52]. Additionally, animal studies have suggested that the upregulation of hepatocyte cytidine/uridine monophosphate kinase 2 and alcohol binge-induced neutrophil extracellular traps can promote MASH-related inflammation and fibrosis through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome[53,54]. Inflammatory signals travel through the circulation to the bone marrow, triggering the reprogramming of hematopoietic stem and progenitor cells[55]. These reprogrammed myeloid cells acquire persistent epigenetic and metabolic memory, leading to augmented inflammatory responses[50]. Once entering the circulation, these cells can infiltrate the cardiovascular system and contribute to endothelial dysfunction and atherosclerosis[55]. As revealed by the above findings, the immunometabolic network participates in the expansion of MASLD-associated systemic inflammatory status. However, the causal relationships of each step are predominantly supported by preclinical data and indirect evidence, and full validation in humans requires further investigation.

Gut-derived signaling network: Gut dysbiosis and gut-liver axis dysfunction are another potential pathway for the systemic amplification of the cardio-hepatic axis. Gut microbiota metabolites may not only affect liver function but also contribute to the pathogenesis of metabolic syndrome via multi-organ crosstalk[56]. Animal studies have demonstrated that MASLD-associated dysbiosis reduces tight junction protein expression and increases vascular permeability, enabling bacterial products such as lipopolysaccharide to enter the liver, where they activate Kupffer cell TLR4/NF-κB signaling and trigger oxidative stress[57]. Additionally, the microbial metabolite trimethylamine N-oxide suppresses the sirtuin 3-superoxide dismutase 2 pathway, resulting in mitochondrial reactive oxygen species accumulation, NLRP3 inflammasome activation, and promoted vascular inflammation[58]; human population studies have validated that circulating trimethylamine N-oxide levels are correlated with both cardiac fibrosis and hepatic fibrosis[59]. Moreover, animal studies have indicated that imidazole propionate, a histidine-derived microbial metabolite, can activate pro-inflammatory and pro-atherosclerotic cascades in endothelial tissues[60]. Gut-derived signals can indirectly amplify the cardio-hepatic axis by modulating inflammatory responses. At the population level, a large-scale prospective cohort study reveals that each one-unit elevation in the gut microbiota dietary index correlates with a 19.5% decrease in cardiovascular mortality risk among patients with MASLD[61], providing epidemiological evidence for the association between gut microbiota and cardiovascular prognosis.

Circadian rhythm network: The liver serves as a core hub for circadian rhythm regulation, and circadian disruption in the liver is tightly linked to MASLD[62]. At the population level, patients with MASLD exhibit elevated nocturnal hepatic de novo lipogenesis and endogenous glucose production, accompanied by deteriorated hepatic and peripheral insulin resistance as well as increased systemic non-esterified fatty acid exposure. These metabolic abnormalities are further aggravated under the condition of low nocturnal insulin levels. Notably, such circadian metabolic differences remain persistent after weight loss, indicating that nocturnal metabolic dysfunction acts as a primary driver of steatosis[63]. Mechanistically, interactions exist between circadian rhythms and gut microbiota. Animal experiments confirm that circadian disruption affects microbial composition and intestinal barrier function, thereby exacerbating hepatic inflammation[64]. At the molecular level, FGF1 exhibits circadian expression patterns and modulates daily triglyceride secretion through the fibroblast growth factor receptor 4-mechanistic target of rapamycin complex 1-inositol-requiring enzyme 1-X-box binding protein 1 signaling cascade; liver-specific FGF1 knockout significantly aggravates MASLD[65]. Furthermore, the clock gene brain and muscle ARNT-like 1-casein kinase 1 epsilon-REV-ERBα pathway influences hepatic stellate cell activation by regulating transgelin, and in vitro studies have verified that disruption of circadian locomotor output cycles kaput/brain and muscle ARNT-like 1 or REV-ERB activation suppresses hepatic stellate cell activation[66].

Circadian disturbance in the liver may affect hepatic metabolism and distal organs by circulating metabolites and inflammatory signals. The heart possesses an independent molecular clock for regulating myocardial energy metabolism, contractile function, and vascular tone. Circadian disruption has been tightly correlated with CVD[67]. Hepatic circadian dysregulation in MASLD and cardiovascular circadian disturbances may act in concert. They can collectively drive the systemic pathology of the cardio-hepatic axis. However, this hypothesis should be further tested.

Genetic and epigenetic regulation: Genetic variation and epigenetic reprogramming are correlated with inter-individual variations in disease vulnerability. MASLD exhibits a prominent polygenic architectural feature. Population-based investigations have demonstrated that polygenic risk scores are widely associated with outcomes related to liver function, cardiac metabolism, renal function and the endocrine system[68]; additionally, at least two genetic subtypes have been identified: A liver-restricted subtype (linked to more progressive hepatic lesions) and a systemic subtype (correlated with elevated risks of cardiometabolic disease)[69].

Epigenetic modifications in hepatocytes cover multiple mechanisms including DNA methylation, histone modifications, and non-coding RNAs, through which environmental factors may exert lasting effects[70]. In the heart, metabolic substrates have been verified to modulate the expression of heart failure-associated genes via epigenetic adjustments such as histone acetylation and methylation, thus participating in disease progression[71]. It has been speculated that MASLD may affect gene expression in the vasculature and heart by circulating metabolites. Accordingly, hepatic metabolic disturbances can be linked to the cardiovascular system. Nevertheless, this speculation currently lacks direct evidence.

Clonal hematopoiesis of indeterminate potential (CHIP) describes a phenomenon wherein hematopoietic stem or progenitor cells harboring somatic mutations achieve clonal expansion owing to acquired proliferative advantages. Population-based studies have indicated that CHIP, especially non-DNA methyltransferase 3A and non-ten-eleven translocation 2 mutations, is independently correlated with the risk of MASLD-related hepatocellular carcinoma[72]; however, this observation remains preliminary and exploratory. CHIP and “trained immunity” may jointly constitute a key mechanism of bone marrow-originated inflammation, contributing to the systemic exacerbation of metabolic disorders by regulating the inflammatory secretion of myeloid cells[55]; nonetheless, the above conclusions are mainly drawn from mechanistic speculation and indirect evidence, and their causal relationships need to be validated by prospective clinical studies.

This section summarizes the bidirectional mechanistic framework of the cardio-hepatic axis from three perspectives: Pathogenic signals from the liver to the heart (lipotoxicity, hepatokines, EVs), feedback signals from the heart to the liver (hemodynamic, neurohumoral, and cardiogenic signals), and systemic amplification networks (immunometabolism, gut-derived signals, circadian rhythms, as well as genetic/epigenetic regulation). The key signal mediators of bidirectional cardio-hepatic communication are outlined in Table 1.

Table 1 Signal mediators for bidirectional cardio-hepatic communication in metabolic dysfunction-associated steatotic liver disease.

Signal direction	Signal category	Key mediators/pathways	Target organ(s)	Core biological effects	Pathological outcomes
Liver → heart	Lipotoxic metabolites	FFAs, ceramides, lipotoxic intermediates	Myocardium, vascular endothelium	Induce myocardial lipid overloading; activate STING pathway and inflammatory cascades	Myocardial systolic/diastolic dysfunction, ferroptosis, fibrosis, accelerated atherosclerosis
	Hepatokines	FGF21	Heart, adipose tissue	Improve myocardial mitochondrial function; endogenous upregulation marks metabolic stress	Dual effects: Cardioprotective in preclinical models; high circulating level predicts elevated MACE risk
	Hepatokines	FXI	Heart, systemic circulation	Circulatory prothrombotic activity; local cardiac anti-inflammatory, anti-fibrotic non-coagulant function	Higher thrombosis and cardiovascular risk; ameliorated diastolic dysfunction and ventricular remodeling
	Hepatokines	PCSK9	Vascular endothelium, myocardium	Elevate LDL-C; promote LDL-C-independent vascular inflammation	Accelerated atherosclerosis; cardiac lipid/mitochondrial damage (species-specific discrepancy)
	Hepatokines	ANGPTL3, SAA1/4	Vascular endothelium, myocardium	ANGPTL3 suppresses lipid clearance; SAA1/4 trigger NF-κB/TGF-β profibrotic signaling	Increased atherosclerotic risk; aggravated myocardial fibrosis
	H-EVs	miR-1, miR-30b-5p, miR-3075	Vascular endothelium, systemic tissues	miR-1/30b-5p inhibit KLF4 and drive inflammation; miR-3075 modulates insulin sensitivity	Vascular inflammation, worsened atherosclerosis, systemic insulin resistance
Heart → liver	Hemodynamic pathways	CVP elevation, hepatic venous congestion, mechanical stretch, hepatic sinusoidal thrombosis	HSCs, hepatic sinusoidal endothelium	Mechanical tension activates HSCs; induce intrahepatic microthrombosis	Increased liver stiffness, progressive hepatic fibrosis, elevated portal pressure
	Neurohumoral pathways	RAAS, SNS	HSCs, hepatocytes	Ang II induces HSC contraction and proliferation; SNS disturbance disrupts hepatic lipid metabolism and perfusion	Aggravated hepatic inflammation, excessive collagen deposition, progressive fibrosis
	Cardiac endocrine factors	ANP, BNP	Adipose tissue, liver	Promote white adipocyte browning; indirect regulation of systemic energy homeostasis	Reduced systemic metabolic burden; no direct hepatic regulatory activity
	Cardiac endocrine factors	GDF15	Liver, adipose tissue	Improve hepatic insulin sensitivity; reprogram macrophages to relieve fibrosis	Attenuated steatosis/inflammation; circulating GDF15 serves as HF biomarker
Systemic amplification network	Immunometabolic regulators	DAMPs, PAMPs, MIF, NLRP3	Liver, bone marrow, vascular endothelium	Trigger hepatic M1 macrophage polarization; remodel hematopoietic stem cells	Exacerbated hepatic inflammation; myeloid-mediated endothelial injury and atherosclerosis
	Gut microbiota-derived metabolites	TMAO, imidazole propionate	Liver, vessels, myocardium	Activate hepatic TLR4; inhibit SIRT3 and stimulate NLRP3 inflammasome	Severe hepatic inflammation/fibrosis; vascular and myocardial fibrotic lesions
	Circadian rhythm regulators	BMAL1, REV-ERBα, FGF1	Liver, heart	Control hepatic DNL and gluconeogenesis; sustain cardiac clock function	Synchronized cardio-hepatic circadian disruption, aggravated systemic cardiometabolic injury
	Genetic/epigenetic regulators	PNPLA3, HSD17β13, CHIP	Liver, cardiovascular system	Boost hepatic steatosis susceptibility; perpetuate chronic liver injury	Higher coronary atherosclerotic risk; bone marrow-derived inflammatory cardiac damage

H-EVs: Hepatocyte-derived extracellular vesicles; FFAs: Free fatty acids; STING: Stimulator of interferon genes; FGF21: Fibroblast growth factor 21; MACE: Major adverse cardiovascular event; FXI: Factor XI; PCSK9: Proprotein convertase subtilisin/kexin type 9; LDL-C: Low-density lipoprotein cholesterol; ANGPTL3: Angiopoietin-like protein 3; SAA1/4: Serum amyloid A 1/4; NF-κB: Nuclear factor-κB; TGF-β: Transforming growth factor-beta; KLF4: Kruppel-like factor 4; CVP: Central venous pressure; HSCs: Hepatic stellate cells; RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system; Ang II: Angiotensin II; ANP: Atrial natriuretic peptide; BNP: Brain natriuretic peptide; GDF15: Growth differentiation factor 15; HF: Heart failure; DAMPs: Damage-associated molecular patterns; PAMPs: Pathogen-associated molecular patterns; MIF: Macrophage migration inhibitory factor; NLRP3: NOD-like receptor pyrin domain-containing 3; TMAO: Trimethylamine N-oxide; TLR4: Toll-like receptor 4; SIRT3: Sirtuin 3; FGF1: Fibroblast growth factor 1; DNL: De novo lipogenesis; PNPLA3: Patatin-like phospholipase domain-containing 3; HSD17β13: Hydroxysteroid 17-beta dehydrogenase 13; CHIP: Clonal hematopoiesis of indeterminate potential.

RISK STRATIFICATION OF THE CARDIO-HEPATIC AXIS IN MASLD

Fibrosis stage is the strongest predictor of prognosis in MASLD. In the largest global biopsy-proven MASLD cohort (17792 patients), the prevalence of advanced fibrosis (≥ F3) is 35%, with the prevalence of diabetes increasing from 28% at the F0 stage to 70% at the F4 stage, and 5-year mortality rising from 2.1% in the overall population to 8.3% in patients with cirrhosis, exceeding 10% in patients stratified as high-risk based on non-invasive fibrosis markers[73]. Data from a large United States real-world cohort of patients with steatotic liver disease (366433 patients) show that CVD constitutes the leading cause of death in patients with MASLD, with the 10-year cumulative cardiovascular mortality rate reaching 8.1% in the non-cirrhotic stage and 17.3% in the cirrhotic stage[74]. Subclinical alterations including left ventricular diastolic dysfunction and impaired myocardial deformation have also been observed prior to the development of overt CVD[75]. An international multidisciplinary Delphi consensus has formally recognized MASLD as a risk-enhancing factor for atherosclerotic CVD[76]. The above evidence indicates that the severity of liver fibrosis and cardiovascular risk demonstrate a parallel and incremental relationship in patients with MASLD, and the assessment of both dimensions should be integrated into stratified clinical management.

Risk stratification for liver fibrosis: International guidelines consistently recommend a two-step screening strategy[77,78]. The fibrosis-4 (FIB-4) index is a guideline-recommended first-line point-of-care screening tool: Values < 1.3 rule out advanced fibrosis, whereas values > 2.67 indicate a high risk of advanced fibrosis (the tool yields a low positive predictive value in primary care settings, necessitating second-line confirmatory testing)[77-79]. Patients with FIB-4 values between 1.3 and 2.67 should receive second-line testing, such as vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test, to clarify the severity of liver fibrosis. VCTE generates liver stiffness measurement values: Values < 8 kPa rule out advanced fibrosis, while values ≥ 12 kPa confirm advanced fibrosis; the controlled attenuation parameter thresholds for steatosis grading are defined as S1 ≥ 248 dB/m, S2 ≥ 268 dB/m, and S3 ≥ 280 dB/m[80]. In patients with obesity, the XL probe can improve the success rate of VCTE measurements[80]; when VCTE is unavailable, an ELF score ≥ 9.8 serves as a valid alternative[77,78]. The 2026 JSH guidelines specify the following referral criteria: FIB-4 > 2.67; FIB-4 values of 1.3-2.67 (≥ 2.0 in individuals aged ≥ 66 years) accompanied by any non-invasive liver disease assessment result above the cutoff value; platelet count < 200000/μL; or persistently elevated liver enzyme levels[78]. International guidelines recommend that low-risk patients (FIB-4 < 1.3) undergo reassessment every 2-3 years, while high-risk patients [those with type 2 diabetes mellitus (T2DM) or established CVD] receive annual reassessment[76,77]. Notably, the FIB-4 index has clinical limitations: In patients with T2DM, its false-negative rate reaches 38%[81]; additionally, its diagnostic accuracy is compromised in individuals aged < 35 years and > 65 years (a modified threshold of > 2.0 is recommended for patients aged ≥ 65 years)[76].

Cardiovascular risk assessment in patients with MASLD: International cardiovascular expert consensus advises that all patients with MASLD, irrespective of traditional risk factors, should receive cardiovascular risk evaluation. To be specific, the evaluation is conducted via standard atherosclerotic CVD risk prediction tools (e.g., the AHA PREVENT equation) with annual screening for T2DM, hypertension, and dyslipidemia[76]. The PREVENT equation was established based on datasets of more than 6 million participants, exhibits better calibration capacity relative to the Pooled Cohort Equations, and delivers stable predictive performance across different racial and ethnic groups[82,83]. However, simulation studies have indicated that adherence to conventional statin treatment thresholds could result in nearly 14 million individuals losing their treatment eligibility[82]. Accordingly, MASLD should be recognized as a risk-augmenting factor in affected patients, and personalized clinical decisions should incorporate coronary artery calcium (CAC) scoring for individuals with borderline or intermediate-risk[84]: A CAC score of 0 may downgrade risk classification, while a CAC score ≥ 100 AU or ≥ 75^th percentile may upgrade risk classification[84].

Predictive value of liver fibrosis markers for cardiovascular risk: Apart from its application in liver fibrosis evaluation, FIB-4 has been validated in multiple large observational studies as an independent predictor of cardiovascular endpoints. A nationally representative population survey in the United States (19695 participants) revealed that FIB-4 ≥ 2.67 correlates with a higher prevalence of heart failure[85]. A large cohort study enrolling 6563 patients with acute coronary syndrome demonstrated that elevated FIB-4 levels are linked to increased risks of major adverse cardiovascular and cerebrovascular events, all-cause mortality, and myocardial infarction[86]. Data from multi-ethnic community-based cohorts further verified that liver fibrosis markers are strongly correlated with a medical history of atrial fibrillation and heart failure; nevertheless, such correlation with coronary heart disease is weakened after adjustment for CAC score, indicating that this association is partially mediated by atherosclerosis[87]. Notably, the independence of this correlation remains controversial. Mendelian randomization analyses have confirmed a causal relationship between hypertension and MASLD[88], while mechanistic investigations in animal and cell models have proven that myocardial infarction can accelerate MASH fibrosis[89]. For this reason, FIB-4 results should be interpreted together with conventional risk indicators, instead of being treated as a standalone causal risk factor. Existing clinical evidence supports the adoption of fibrosis screening outcomes as a critical reference for CVD risk assessment in MASLD patients, rather than a replacement for standard cardiovascular examination.

Integrated framework for combined cardio-hepatic risk stratification: Based on the above evidence regarding fibrosis screening and cardiovascular risk evaluation, liver fibrosis risk (FIB-4/VCTE/ELF) and CVD risk (PREVENT/CAC) form two complementary dimensions of comprehensive risk assessment for MASLD patients. This framework integrates the two dimensions into three clinical decision tiers (Figure 2). In brief, MASLD is a systemic cardiometabolic disease, and CVD is its leading cause of death. As a simple first-line tool, FIB-4 constitutes an accessible entry point for combined cardio-hepatic stratification in MASLD. However, the applicability of the above framework across different populations and its effect on improving clinical outcomes require prospective validation.

Figure 2 Integrated cardio-hepatic risk stratification workflow for metabolic dysfunction-associated steatotic liver disease. All patients receive annual screening for type 2 diabetes mellitus, hypertension and dyslipidaemia plus baseline atherosclerotic cardiovascular disease risk assessment via the PREVENT equation. Step 1: Fibrosis-4 (FIB-4) index initial fibrosis screening (low: FIB-4 < 1.3; grey zone: 1.3 ≤ FIB-4 ≤ 2.67; high: FIB-4 > 2.67). Grey zone patients proceed to vibration-controlled transient elastography liver stiffness measurement (LSM) measurement (exclude advanced fibrosis: LSM < 8 kPa; grey zone: 8 kPa ≤ LSM < 12 kPa; advanced fibrosis: LSM ≥ 12 kPa); enhanced liver fibrosis score (cutoff ≥ 9.8) serves as a vibration-controlled transient elastography substitute. Three management tiers are defined: (1) Routine biennial follow-up for low-risk patients; (2) Annual monitoring with coronary artery calcium recalibration for intermediate-risk individuals; and (3) Urgent multidisciplinary specialist referral for high-risk patients. All patients with type 2 diabetes mellitus or established cardiovascular disease require yearly fibrosis reassessment. XL probe is suggested for obese patients to measure controlled attenuation parameter steatosis grade simultaneously. MASLD: Metabolic dysfunction-associated steatotic liver disease; T2DM: Type 2 diabetes mellitus; FIB-4: Fibrosis-4; ELF: Enhanced liver fibrosis; LSM: Liver stiffness measurement; CVD: Cardiovascular disease; CAC: Coronary artery calcium; VCTE: Vibration-controlled transient elastography.

THERAPEUTIC STRATEGIES FOR MASLD THROUGH MODULATION OF THE CARDIO-HEPATIC AXIS

Reducing forward liver-to-heart injury

Targeting lipotoxicity and metabolic reprogramming: Lifestyle intervention constitutes the cornerstone of clinical management for MASLD and its related cardiovascular disorders. Population-based investigations have indicated that 5%-7% body weight loss can ameliorate hepatic steatosis and necroinflammation, whereas weight loss exceeding 10% can trigger MASH resolution and reverse liver fibrosis[90,91], accompanied by an approximate 20% reduction in the risk of major composite cardiovascular endpoints[92]. The Mediterranean diet and regular physical activity (150 minutes per week of moderate-intensity exercise) act as adjunctive strategies to weight reduction, which ameliorates insulin resistance and lowers coronary heart disease risk, respectively[93,94]. For individuals with severe obesity, a meta-analysis on bariatric surgery has revealed a correlation with decreased all-cause and cardiovascular mortality[95].

Glucagon-like peptide-1 (GLP-1) receptor agonists confer dual protective effects on the liver and cardiovascular system via weight loss promotion and insulin sensitivity amelioration. In a phase III clinical trial, semaglutide 2.4 mg markedly improved MASH histological outcomes, yielding a resolution rate of 62.9% and fibrosis amelioration in 36.8% of enrolled patients[96]; the SELECT trial, which recruited overweight or obese patients with pre-existing CVD but no diabetes, verified that semaglutide reduces the incidence of major adverse cardiovascular events (MACE)[97]. On the basis of two large-scale randomized controlled trials (RCTs), semaglutide is currently one of the most well-validated pharmacological agents that exert both MASH fibrosis improvement and cardiovascular benefits.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist (GLP-1RA), showed improved MASH resolution and fibrosis regression following 52 weeks of treatment in a phase II trial[98]. Indirect comparative analyses based on data from the SURPASS-cardiovascular outcome trial (CVOT) and REWIND trials estimated that tirzepatide reduces the risk of MACE-3 by roughly 28% and all-cause mortality by around 39% relative to placebo[99]; nevertheless, these estimations originate from pre-specified exploratory analyses, and the reliability of its cardiovascular benefits requires further verification from the final direct outcomes of the SURPASS-CVOT trial. To date, the hepatic protective effects of tirzepatide are supported by phase II clinical data, while its cardiovascular benefits are derived from computational modeling analyses; the evidence level of its “dual benefit” is intermediate between semaglutide and resmetirom.

Resmetirom, an oral partial thyroid hormone receptor-β agonist, obtained FDA approval in 2024 for the treatment of non-cirrhotic MASH with F2-F3 stage fibrosis. The phase III MAESTRO-NASH trial demonstrated that 52-week treatment with 100 mg resmetirom achieved a MASH resolution rate of 29.9% and a fibrosis improvement rate of 25.9%; however, its cardiovascular benefits remain to be validated by the MAESTRO-Outcomes Cardiovascular Outcomes Trial (CVOT)[100]. Current available evidence indicates that resmetirom is primarily indicated for patients with F2-F3 hepatic fibrosis. Its liver-protective efficacy has been validated in phase III RCTs, whereas its cardiovascular advantages still require prospective verification via the MAESTRO-Outcomes CVOT.

Lanifibranor, a pan-PPAR agonist, achieved superior MASH resolution and fibrosis amelioration compared with placebo in the phase IIb NATIVE trial. For patients with high baseline cardiovascular risk (35%-44%), their cardiovascular risk scores were reduced to low-to-moderate levels after lanifibranor treatment[101]. It is noteworthy that this endpoint is a risk score (a surrogate endpoint) rather than a hard cardiovascular outcome. Pioglitazone, a PPARγ agonist, has been shown to improve MASH resolution and fibrosis stage. However, the risks of fluid retention, cardiac decompensation, and fracture limit its broad application in patients with concurrent cardio-hepatic disease[102].

Modulation of hepatokine-derived endocrine signals: FGF21 analogs represent one of the more progressive directions in hepatokine-targeted therapy. In a phase IIb trial of patients with F2-F3 fibrosis, efruxifermin 50 mg once weekly for 96 weeks attained a fibrosis improvement of ≥ 1 stage in 49% of the modified intention-to-treat population and in 75% of the subgroup of patients who finished biopsy[103]; in F4 cirrhosis, the primary endpoint was not achieved at 36 weeks, yet exploratory endpoints at 96 weeks indicated potential delayed benefits[104], implying that fibrosis reversal may require a sufficiently long intervention window. A network meta-analysis further endorsed the fibrosis-improving effects of efruxifermin; pegozafermin exhibited a numerically higher effect size in this analysis[105], and its phase III trial is presently ongoing.

PCSK9 inhibitors have been demonstrated to further lower myocardial infarction by approximately 21% and stroke by approximately 23% in addition to statin therapy[106]. Unlike FGF21 analogs, the cardiovascular benefits of PCSK9 inhibitors have been strongly validated by multiple large-scale cardiovascular outcomes trials; however, their drawback is that they cannot directly improve hepatic histology, and thus their application in patients with MASLD should be guided by individualized assessment of both hepatic and cardiovascular risk.

In addition to the above hepatokine-targeted strategies that have entered clinical development, ANGPTL3 inhibitors, FXI, and SAA, which were described as hepatokine targets in the mechanisms section, are at diverse stages of therapeutic development in the cardio-hepatic comorbidity field. Although ANGPTL3 inhibitors have been approved for homozygous familial hypercholesterolemia, no data are available on their hepatic histologic benefit in patients with MASLD, and their cardiovascular benefit is mainly derived from genetic speculation and lipid-lowering biomarkers, without cardiovascular outcome RCT validation in the cardio-hepatic comorbidity setting. For FXI and SAA-targeted therapies, there are currently no clinical data on cardiovascular protection specifically in patients with MASLD; moreover, mechanistic studies have indicated that FXI may have non-coagulant-dependent functions locally in the heart, and whether its inhibition requires vigilance for potential cardiac risks remains to be explored in clinical studies. SAA currently has no direct targeted agent that has entered clinical development, and its therapeutic translation stays in the early exploratory stage.

Targeting EVs: Therapeutic strategies targeting EV signaling are all at the preclinical stage. Current efforts are mainly directed toward two approaches: Blocking pathogenic EV signals and engineering EVs as therapeutic delivery vehicles. In animal studies, an anti-miR-1 strategy has been demonstrated to block hepatic EV-mediated vascular inflammation and atherosclerotic effects[35]. Engineered EVs loaded with FGF21 or miR-223 have displayed multi-target therapeutic potential in MASH animal models, and liver-targeted delivery may avoid systemic side effects[107]. However, difficulties including EV heterogeneity, targeting specificity, and large-scale production still pose substantial barriers to clinical translation[108].

Reducing feedback heart-to-liver injury

Improving venous congestion and hypoperfusion: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are typical agents that connect cardiac benefits and hepatic metabolic amelioration. In patients with HFpEF, a population-based RCT showed that dapagliflozin treatment for 24 weeks enhanced total arterial compliance and venous capacitance during exercise[109]. In the liver, dapagliflozin has been found to decrease hepatic fat content in patients with T2DM and MASLD in a population-based RCT adopting imaging endpoints[110]; however, this endpoint is an imaging-based surrogate marker and lacks histological verification. With regard to cardiovascular outcomes, SGLT2i have been proven to lower MACE by approximately 11% and hospitalization for heart failure by approximately 23%, with cardiorenal benefits strongly validated in multiple large-scale CVOTs[111]. Based on the existing evidence, SGLT2i are applicable for patients with MASLD who have concurrent overt cardiac dysfunction or risk of heart failure, with clear merits for heart failure hospitalization, yet the evidence for hepatic histological improvement remains inadequate.

Inhibiting neurohumoral activation: The utility of RAAS inhibitors [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] in patients with MASLD is mainly derived from observational studies, and the evidence remains debatable. A retrospective analysis utilizing the TriNetX national database showed that, relative to calcium channel blockers, ACEI/ARB were linked with a concurrent reduction in the risk of all-cause mortality, major adverse liver outcomes, and MACE[112]. The UK Biobank cohort indicated that ARB were superior to ACEI in boosting survival and reducing cardiovascular events in patients with MASLD[113]; however, a meta-analysis that mainly enrolled patients with diabetes showed that ACEI were superior to ARB in lowering all-cause mortality, cardiovascular mortality, and MACE[114]. This inconsistency indicates that the relative merits of ACEIs and ARBs may vary across patient populations. The potential advantage of ARB in patients with a high burden of hepatic events requires further verification, while the cardiovascular evidence for ACEI is more solid in patients with diabetes. Based on the existing observational evidence, ACEI/ARB may be considered for patients with MASLD who have concurrent hypertension or high cardiovascular risk; however, RCTs are required to verify their specific merits in this patient population.

Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, earns attention based on preliminary evidence in patients with MASLD and concurrent chronic kidney disease (CKD). In a prespecified subgroup analysis of the FIDELITY trial, the cardiovascular benefits of finerenone were found to be intensified in patients at high risk of liver fibrosis (elevated FIB-4)[115]; however, this finding is preliminary and requires prospective verification. Therefore, the clinical value of finerenone in patients with MASLD remains preliminary and is not recommended for routine clinical use; in individuals with concurrent CKD and high risk of liver fibrosis, it may be regarded as a potential personalized therapeutic option, yet additional evidence is required to support its clinical application.

Modulating cardiogenic endocrine signals: The heart reciprocally regulates hepatic metabolism via the secretion of cardiogenic factors including ANP, B-type natriuretic peptide, and GDF15. Animal investigations have verified that GDF15 alleviates steatosis, inflammation, and fibrosis in MASH through directly inhibiting the expression of fibrotic genes and osteopontin in hepatic stellate cells[116]. At present, no pharmaceutical agent directly targeting cardiogenic signals has been approved for MASLD treatment; this research direction stays at the preclinical exploratory stage and serves as a promising avenue for cardio-hepatic axis drug development, yet it is not yet suitable for clinical application.

Network-targeted therapies to remodel systemic amplification

Targeting inflammatory pathways: Interventions targeting systemic inflammatory pathways have drawn research attention in the field of cardio-hepatic comorbidity, while most relevant evidence remains preliminary. Aspirin is in the early exploratory phase for MASLD management. A phase II RCT revealed that low-dose aspirin yielded a relative hepatic fat reduction of ≥ 30% in 42.5% of MASLD patients (an imaging-based surrogate endpoint)[117]; nevertheless, this outcome requires histological confirmation, and aspirin is not advised for routine clinical use at present. The interleukin-1β pathway-targeted anti-inflammatory strategy, as validated in the CANTOS trial, was the first approach to prove in cardiovascular research that anti-inflammatory treatment could lower MACE independent of lipid lowering; however, it failed to obtain clinical approval owing to infectious risks and neutral all-cause mortality[118], and no direct data support its application in MASLD. Colchicine has exhibited favorable MACE outcomes in patients with coronary heart disease (confirmed by meta-analysis subgroup evaluation), yet no direct evidence has been established in MASLD[119]. The C-C chemokine receptor type 2/type 5 dual antagonist cenicriviroc attained a 20% fibrosis improvement rate in the phase IIb CENTAUR trial, whereas the subsequent phase III AURORA trial was prematurely terminated due to futility[120], and the clinical development of this agent for NASH has been largely suspended. In brief, no anti-inflammatory or anti-fibrotic agents have been approved for the treatment of MASLD-related cardio-hepatic comorbidity; aspirin and colchicine lack dedicated MASLD clinical evidence, cenicriviroc development is mostly discontinued, and the anti-interleukin-1β strategy cannot be clinically translated due to safety issues. None of the aforementioned strategies are currently viable for clinical practice.

Modulating gut microbiota and bile acid signaling: Gut dysbiosis and bile acid metabolic disorders constitute key links in the systemic amplification network of the cardio-hepatic axis. Interventional approaches targeting this network include microbiome-based preparations, farnesoid X receptor (FXR) agonists, and FGF19 analogs, though most relevant clinical evidence remains preliminary. Evidence regarding microbiome-based agents (probiotics/synbiotics) is mainly sourced from a network meta-analysis, which reported that synbiotics exerted the optimal effects on lowering aspartate aminotransferase and LDL-C, whereas probiotics were most effective in reducing alanine aminotransferase (ALT) and triglycerides; nevertheless, neither intervention substantially improved body mass index or insulin resistance[121]. Furthermore, the enrolled RCTs mostly presented a moderate risk of bias, and the endpoints were liver enzymes rather than histological outcomes. Based on current clinical data, microbiome-based agents can be adopted as auxiliary therapy for MASLD, yet they cannot substitute lifestyle intervention or approved pharmacological agents.

A meta-analysis focusing on FXR agonists demonstrated amelioration of liver fibrosis and hepatic fat accumulation in MASLD patients, accompanied by a prominent pruritus adverse reaction profile (37.8% vs 18.7%)[122]. Vonafexor, a second-generation non-bile-acid FXR agonist, produced a ≥ 30% reduction in hepatic fat in 50% of participants after a 12-week phase IIa trial (an imaging-based surrogate endpoint), with a pruritus rate of merely 10% (an 80% reduction relative to obeticholic acid), and also yielded a potential signal of improved renal function (an exploratory observation); however, due to limited sample size, absence of histological endpoints and short follow-up duration, its anti-fibrotic efficacy and long-term safety necessitate phase III verification, and this agent is not yet suitable for clinical application[123]. A meta-analysis of aldafermin, an FGF19 analog, revealed that the likelihood of MASH resolution without fibrosis deterioration was approximately threefold higher [risk ratio (RR) 3.04], the composite endpoint response rate was nearly sixfold higher (RR 5.86), and the probability of ≥ 30% fat reduction was around threefold higher (RR 3.14), with a benign safety profile and no occurrence of pruritus or dyslipidemia; nonetheless, its independent fibrosis-improving effect (RR 1.48) failed to achieve statistical significance[124]. Accordingly, aldafermin exhibits promising efficacy for MASH resolution, while its capacity to reverse liver fibrosis requires validation in large-scale phase III trials. Overall, therapeutic strategies targeting gut microbiota and bile acid signaling for MASLD are all in the early clinical or exploratory phases: Microbiome-based agents can serve as supplementary therapy with limited supporting evidence; FXR agonists remain underdeveloped due to adverse effects and insufficient histological evidence; and the fibrosis-protective effects of aldafermin are yet to be confirmed. None of the above interventions are currently eligible for routine clinical practice.

Restoring circadian rhythms: In general, interventional strategies targeting circadian disruption encompass time-restricted eating (TRE) and melatonin supplementation. The existing evidence for both approaches remains scarce. Further investigation should be conducted for their clinical translation. A meta-analysis of TRE demonstrated improvements in body weight, waist circumference, and fat mass in overweight or obese adults, but yielded only a mild effect on insulin resistance, with uncertain impacts on lipid profiles and fasting glucose; additionally, the absence of liver fat and liver enzyme endpoints leads to a lack of direct evidence in MASLD[125]. The NHANES cohort study (19831 participants) found that a daily eating duration of less than 8 hours was correlated with elevated cardiovascular mortality risk [hazard ratio (HR) 2.35]; nevertheless, due to its observational study design, residual confounding factors cannot be ruled out, and clinical recommendation for such an extreme TRE regimen (less than 8 hours) is not advisable at present[126].

A meta-analysis on melatonin indicated that melatonin (5-20 mg/day) can ameliorate multiple cardiometabolic risk factors, with relatively solid evidence supporting its anti-inflammatory, antioxidant, hypoglycemic and lipid-regulating properties; in contrast, no remarkable changes were detected in body weight, diastolic blood pressure, insulin resistance, or liver enzymes[127]. A small-sample RCT focusing on MASLD patients reported that bedtime melatonin administration lowered liver enzymes, alleviated ultrasound-detected hepatic steatosis grading, and optimized several metabolic indicators[128]; however, the limited sample size and absence of rigorous clinical endpoints restrict the quality of this evidence. Based on current findings, melatonin can act as an auxiliary intervention for cardiometabolic disease, yet it cannot substitute standard pharmacotherapy, and the long-term safety of medicinal doses needs verification via large-scale RCTs.

In summary, clinical evidence supporting TRE and melatonin application in MASLD and its associated cardiovascular risks remains inadequate. Extreme TRE brings potential safety hazards, while the direct protective effects of melatonin on hepatic lesions remain unclear. Neither intervention is currently recommended for regular clinical application.

Targeting genetic and epigenetic regulation: Targeted therapies against genetic susceptibility loci in MASLD constitute an emerging research direction; however, these approaches are currently at very early clinical stages and confront potential safety concerns. Patatin-like phospholipase domain-containing protein 3 (PNPLA3)-targeted therapy addresses one of the strongest genetic risk factors for MASLD (PNPLA3 rs738409 I148M). In a phase I trial, AZD2693 achieved an 89% knockdown of PNPLA3 mRNA, along with decreased hepatic fat content and lowered inflammatory markers in homozygous patients, without serious adverse events or treatment discontinuation[129]. Another PNPLA3-targeting small interfering RNA agent (JNJ-75220795) in a phase I trial demonstrated that a single dose reduced hepatic fat content by approximately 46% at 12 weeks in homozygous MASLD patients, with the therapeutic effect sustained for at least 24 weeks and a benign safety profile; nevertheless, this efficacy was only observed in homozygous carriers, and evidence supporting fibrosis improvement remains absent, rendering subsequent phase II/III trials essential for validating its clinical utility[130]. Mendelian randomization studies have indicated that lifelong PNPLA3 inhibition may elevate the risk of coronary atherosclerosis [odds ratio (OR) 1.14], coronary heart disease (OR 1.14), and myocardial infarction (OR 1.16), with approximately 14%-30% of this adverse effect mediated by elevated LDL-C and total cholesterol levels[131]. This observation carries important safety implications for ongoing PNPLA3-targeted drug trials: MACE endpoints should be prespecified and lipid profiles closely monitored in subsequent studies to comprehensively evaluate the long-term benefit-risk balance.

Hydroxysteroid 17-beta dehydrogenase 13 (HSD17β13)-targeted therapy represents another viable direction for genetic targeting. In a phase I/IIa proof-of-concept trial, the RNA interference therapeutic ARO-HSD achieved approximately 93% knockdown of hepatic HSD17β13 mRNA in MASH patients, accompanied by a roughly 40% reduction in ALT levels, with a favorable short-term safety profile. Nevertheless, evidence regarding histological amelioration (NAS score and fibrosis staging), alterations in hepatic fat content, and long-term safety is still lacking. Phase II validation with liver biopsy-based endpoints will be critical to determine whether this target can be advanced toward clinical application[132].

CHIP is an age-related somatic mutation event occurring in hematopoietic stem cells that has been preliminarily linked to severe adverse outcomes of MASLD. In a large-scale cohort study including 214563 participants, CHIP was found to be correlated with elevated risks of chronic liver disease (OR 2.01), and Mendelian randomization analyses have suggested a potential causal association (OR 2.37), wherein ten-eleven translocation 2 mutation-driven NLRP3 inflammasome activation may serve as one of the underlying mechanisms[133]. However, these findings remain preliminary genetic correlations and cannot yet be developed into clinical therapeutic targets.

In summary, PNPLA3- and HSD17β13-targeted therapies are both at phase I/very early clinical stages, with their clinical efficacy and safety yet to be fully validated; additionally, PNPLA3 targeting presents a potential cardiovascular safety risk. CHIP remains an exploratory genetic finding. It is currently not applicable to clinical intervention.

Combination therapies to enhance synergistic efficacy

Combination therapy constitutes an important direction in the comprehensive management of the cardio-hepatic axis; however, evidence supporting most combined regimens remains insufficient, and therapeutic selection should be individualized according to patients’ dominant pathological characteristics. The combination of a GLP-1RA and an SGLT2 inhibitor is the most well-documented combination strategy based on existing clinical data. A real-world target trial emulation study revealed that, among patients with T2DM and MASLD, combination therapy correlated with an approximately 40% reduced risk of major adverse liver outcomes (HR 0.57-0.61) and a 20%-35% decrease in MACE risk (HR 0.65-0.80) relative to single-agent monotherapy, with therapeutic effects observed as early as 6 months after follow-up initiation; nevertheless, this study adopted an observational design with a short follow-up duration, and its findings require further RCT verification[134]. A retrospective cohort study (n = 2569) indicated that for patients with baseline FIB-4 < 2.67, combination therapy yielded an approximate 24% reduction in the risk of fibrosis progression (HR 0.76) compared with GLP-1RA monotherapy, with particularly prominent benefits in patients with body mass index ≤ 35; however, FIB-4 serves only as a surrogate endpoint, and further histological or RCT validation is essential[135]. Notably, a target trial emulation study based on the TriNetX database (approximately 180000) demonstrated that combination therapy was linked to reduced all-cause mortality (HR 0.522) and composite hepatic outcomes (HR 0.907) vs SGLT2i monotherapy, but unexpectedly elevated MACE risk by roughly 11% (HR 1.106) compared with GLP-1RA monotherapy, which contradicts the results of aforementioned studies. Such discrepancies may stem from database heterogeneity or residual confounding factors, indicating that the MACE-related effects of combination therapy require rigorous RCT validation[136]. Combination therapy is applicable to patients with insufficient therapeutic response to SGLT2i monotherapy (who obtain definite mortality and hepatic benefits from supplementary GLP-1RA treatment); however, for patients with controlled cardiovascular risk under stable GLP-1RA monotherapy, the incremental MACE benefits of adding an SGLT2i are limited, and individualized risk-benefit evaluation is required.

Evidence for the combined use of resmetirom and GLP-1RAs is mainly derived from a secondary subgroup analysis of the phase III MAESTRO-NASH trial. The outcomes confirmed that the histological efficacy of resmetirom on hepatic lesions was not altered by background GLP-1RA or SGLT2i treatment; when patients achieved ≥ 5% body weight loss, the MASH resolution rate rose from 33.8% to 56.6%, and the fibrosis improvement rate increased from 31.5% to 40.6%[137]. Resmetirom is weight-neutral, whereas GLP-1RAs complement its metabolic efficacy via weight reduction, implying potential synergistic effects; nonetheless, the facilitating impact of weight loss requires prospective validation. This combination is not currently recommended as first-line therapy and should only be adopted after individualized assessment.

Evidence for the combination of efruxifermin (an FGF21 analog) and GLP-1RAs is derived solely from a small phase IIb proof-of-concept trial (n = 31, 12 weeks). As indicated by the results, in patients with T2DM and MASH fibrosis who were on stable GLP-1RA therapy, the addition of efruxifermin led to an additional 65% reduction in hepatic fat fraction (compared with a -10% reduction with GLP-1RA alone), along with improvements in liver injury biomarkers including ALT and Pro-C3 (N-terminal pro-peptide of type III collagen), while body weight remained unchanged[138]. The above-mentioned findings support a “complementary orthogonal” combination strategy for FGF21 analogs and GLP-1RAs. However, the very small sample size and the lack of liver biopsy endpoints limit the level of evidence, and large-scale phase III histological validation is urgently required. This combination strategy remains exploratory at present and is not recommended for routine clinical use.

In summary, the direction of combination therapy in the management of cardio-hepatic comorbidity in MASLD is clear, whereas the evidence remains immature: Observational evidence for GLP-1RA + SGLT2i is relatively substantial; resmetirom + GLP-1RA has synergistic potential based on phase III subgroup analyses; and efruxifermin + GLP-1RA is currently limited to clinical research settings. However, studies specifically targeting cardiovascular benefit are scarce, and the long-term efficacy of combination therapy for hard clinical endpoints such as MACE and cirrhosis progression requires prospective RCT validation. Clinical decisions should be individualized based on the patient’s predominant pathological features, and widespread routine clinical use is not recommended. All therapeutic interventions illustrated in Figure 3, including their applicable populations, hepatic and cardiovascular benefits, evidence grades and remaining limitations, are systematically summarized in Table 2.

Figure 3 Mechanism-targeted therapeutic strategies for cardio-hepatic crosstalk in metabolic dysfunction-associated steatotic liver disease. Central panel: Bidirectional cardio-hepatic pathogenic signalling loops. Four therapeutic modules encircle the core: (1) Upper left: Agents blocking liver-derived pathogenic mediators; (2) Upper right: Therapies reversing heart-induced hepatic injury; (3) Lower left: Interventions suppressing systemic amplification pathways; (4) Lower right: Synergistic combination regimens. Key therapeutic agents are listed within each corresponding module. Full molecular mediators are detailed in Table 1; evidence grading of each intervention is summarised in Table 2. GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent insulinotropic polypeptide; THR-β: Thyroid hormone receptor-β; pan-PPAR: Pan-peroxisome proliferator-activated receptor; PPARγ: Peroxisome proliferator-activated receptor-γ; FGF21: Fibroblast growth factor 21; PCSK9: Proprotein convertase subtilisin/kexin type 9; EVs: Extracellular vesicles; SGLT2: Sodium-glucose cotransporter 2; RAAS: Renin-angiotensin-aldosterone system; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; MRA: Mineralocorticoid receptor antagonist; GLP-1RA: Glucagon-like peptide-1 receptor agonist; SGLT2i: Sodium-glucose cotransporter 2 inhibitor; FXR: Farnesoid X receptor; RNAi: RNA interference; PNPLA3: Patatin-like phospholipase domain-containing protein 3; HSD17β13: Hydroxysteroid 17-beta dehydrogenase 13.

Table 2 Therapeutic interventions targeting the cardio-hepatic axis in metabolic dysfunction-associated steatotic liver disease.

Intervention category	Intervention regimen	Eligible population criteria	Key hepatic outcomes	Key cardiovascular outcomes	Evidence grade (A-E)	Combination and sequential use recommendations	Core limitations and knowledge gaps	Ref.
Non-pharmacological interventions	Lifestyle-induced weight loss	Overweight/obese MASLD patients	↓ hepatic fat, MASH activity, liver fibrosis	↓ composite cardiovascular event risk	C	Foundation for all drug therapies; prioritize weight management first	Small single-center cohorts; short follow-up; idealized trial populations; lack placebo control	[90-92]
	Mediterranean diet	All MASLD patients without dietary contraindications	Improved FLI surrogate	No validated cardiovascular hard endpoints	A	Synergistic with weight loss + regular exercise	Only 6 small RCTs; FLI not biopsy-verified; no long-term histological data	[93]
	Regular physical activity	MASLD patients with cardiometabolic comorbidities	No direct histological benefits	↓ coronary heart disease risk	A	Combined with diet and weight control	Self-reported activity bias; inconsistent exercise quantification; no liver hard endpoints	[94]
	Time-restricted eating	BMI ≥ 25 kg/m2; no eating disorders/GI severe disease	Improved HOMA-IR (metabolic surrogate only)	Narrow < 8 hours fasting links to higher cardiovascular mortality	C	Adjunct lifestyle tool; avoid extreme short feeding windows	High cross-trial heterogeneity; no liver histology/imaging endpoints	[125]
	Bariatric surgery	Severe obesity without surgical contraindications	Indirect liver improvement via massive weight loss	↓ cardiovascular mortality and metabolic disorders	A	Reserved for lifestyle/drug-refractory obesity; not first-line	All observational cohorts; unadjusted confounders; insufficient long-term safety data	[95]
FDA-approved agents for MASH indication	Semaglutide (GLP-1RA)	Non-cirrhotic F2-F3 MASH; exclude F4 cirrhosis; BMI ≥ 27 with CVD	Resolve MASH; reduce liver fibrosis	↓ MACE risk	B	First-line monotherapy; add SGLT2i for T2DM/HF/CKD; switch to resmetirom for week-24 non-responders	Only interim follow-up; Asian population underrepresented; cardiovascular endpoints as secondary exploratory outcomes	[96,97]
	Resmetirom (THR-β agonist)	Non-cirrhotic F2-F3 MASH; exclude F4 cirrhosis	Resolve MASH; improve fibrosis	↓ LDL-C; dedicated CVOT results pending	B	Sequential alternative for semaglutide intolerance; safely combined with GLP-1RA/SGLT2i in T2DM	Short 52-week trial; rare DILI risk; no F4 cirrhosis efficacy data	[100]
Off-label dual cardio-hepatic agents	Tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide dual agonist)	F2-F3 MASH; priority for obese T2DM	Resolve MASH; alleviate fibrosis	MACE benefit inferred from statistical modeling	B	Monotherapy substitute for semaglutide; add SGLT2i for T2DM; avoid dual GLP-1 co-use	Small phase II trials; fibrosis data via imputation; no dedicated cardiovascular hard endpoint trials	[98,99]
	Dapagliflozin (SGLT2i)	MASLD combined with T2DM/HF/CKD (all LVEF)	↓ hepatic fat and ALT	↓ MACE and HF hospitalization risk	B	Only for combined GLP-1RA use in complicated MASLD; monotherapy not recommended for isolated steatosis	Liver benefits rely solely on MRI-LFC surrogates; off-label for MASH; genital infection and volume depletion risks	[109-111]
	Pioglitazone (PPAR-γ agonist)	Prediabetes/T2DM-related MASH; no bladder cancer/severe HF	↓ NAS, resolve MASH, reduce fibrosis	Improve secondary cardiovascular endpoints (MI, cardiovascular death)	B	Monotherapy only for T2DM-MASH; forbidden to combine with other PPAR agonists	Small single-center cohorts; weight gain; bladder cancer black box warning; no F4 cirrhosis data	[102]
	RAAS inhibitors (ACEI/ARB)	MASLD with hypertension/HF/CKD; exclude hyperkalemia/bilateral renal artery stenosis	↓ major adverse liver outcomes	↓ MI and MACE incidence	C	Baseline concurrent therapy for hypertensive MASLD; combined with specific MASH drugs	Retrospective database data; MASLD defined by ICD coding without biopsy; no proven histological improvement	[112-114]
	Statin + PCSK9 inhibitor	Secondary ASCVD prevention	No hepatic therapeutic endpoints	↓ MI and stroke risk	A	Fixed combination for secondary ASCVD only; add colchicine for high-risk patients; not for isolated MASLD	Zero liver hard endpoints; no all-cause mortality reduction	[106]
	Colchicine	Secondary ASCVD prevention; no severe GI/bleeding disease	No hepatic therapeutic endpoints	↓ MI and revascularization risk	B	Adjunct statin/PCSK9i for ASCVD; no independent liver treatment value	No MASLD-specific liver endpoints; frequent GI adverse events; no all-cause mortality benefit	[119]
	Low-dose aspirin	Non-cirrhotic MASLD without bleeding tendency	Mild hepatic fat reduction	No long-term cardiovascular hard endpoint data	B	Exploratory auxiliary steatosis therapy; long-term routine use not advised	Single small phase II trial; no liver biopsy evidence; only 6-month follow-up	[117]
	Finerenone	T2DM + CKD with elevated FIB-4	Neutral to liver enzymes/fibrosis markers	↓ composite MACE risk	B	Reserved only for CKD-complicated T2DM MASLD; purely cardioprotective without liver efficacy	Benefit only from CKD post-hoc subgroup analysis; cannot extend to non-CKD patients	[115]
Investigational MASH targeted agents	Lanifibranor (pan-PPAR agonist)	Non-cirrhotic active MASH (SAF-A ≥ 2, F1-F3)	↓ SAF-A score, resolve MASH, reduce fibrosis	No cardiovascular hard endpoint data	B	Limited to clinical trials; no routine clinical approval	Short 24-week phase IIb; failed phase III primary endpoints; no dedicated cardiovascular trial plan	[101]
	Efruxifermin (FGF21 analog)	F2-F3 MASH; priority for T2DM on stable GLP-1RA	Significant fibrosis regression	No cardiovascular hard endpoint data	B	Not used as monotherapy; exploratory add-on for GLP-1RA partial responders	Small phase IIb cohort; incomplete biopsy data; no efficacy signal for F4 cirrhosis	[103,104]
	Cenicriviroc (CCR2/CCR5 antagonist)	F1-F3 MASH	Mild fibrosis improvement without MASH resolution	No cardiovascular hard endpoint data	B	Clinical development terminated; only for trial reference	Phase III stopped for futility; no large confirmatory trials	[120]
	FXR agonists (OCA, Vonafexor)	F1-F4 MASLD	↓ hepatic fat, ALT and fibrosis markers	Mild HDL-C reduction, potential atherosclerotic risk	B	Poor risk-benefit; not recommended for routine clinical use	Severe pruritus; elevated ALP/DILI risk; only imaging surrogate endpoints	[122,123]
	Aldafermin (FGF19 analog)	F1-F3 MASH	Improved MASH resolution signals	No cardiovascular hard endpoint/Lipid data	A	Only for clinical trial exploration	Pooled 4 small RCTs; fibrosis benefit statistically insignificant; short intervention cycle	[124]
	PNPLA3-targeted oligonucleotides	Homozygous PNPLA3 I148M high-risk MASH	↓ MRI-PDFF hepatic fat	Long-term inhibition may raise CAD risk	B	Pure research agent; strict cardiovascular lipid monitoring required	Early phase I only; narrow applicable genotype; MR analysis suggests proatherogenic risk	[129,130]
	ARO-HSD (HSD17β13-targeted RNA interference)	Non-cirrhotic MASH; exclude F4 cirrhosis	Significant ALT reduction	No cardiovascular hard endpoint data	B	Only exploratory clinical trial drug	Small open-label phase I/II; short pharmacodynamic observation; no long-term histology/safety data	[132]
Anti-inflammatory therapy	Canakinumab (anti-IL-1β mAb)	Prior MI ASCVD patients with hs-CRP ≥ 2 mg/L	No hepatic therapeutic endpoints	↓ composite MACE risk	B	Adjunct for secondary ASCVD only; no MASH-specific indication	Uncertain dose-effect relationship; increased fatal infection risk; high cost	[118]
Gut microbiota intervention	Probiotics/prebiotics/synbiotics	Adult MASLD without severe GI disease	↓ AST, ↓ ALT	Only indirect metabolic improvement; no cardiovascular hard endpoints	B	Auxiliary lifestyle add-on; cannot replace core pharmacotherapy	Huge strain/dosage heterogeneity; only liver enzyme surrogates, no biopsy gold standard	[121]
Dietary supplement	Melatonin	Metabolic syndrome/T2DM/obese MASLD without sleep disorders	Mild ALT reduction, no histology/imaging proof	Minor reduction of SBP, LDL, fasting glucose	B	Auxiliary nutritional supplement; no formal MASH treatment approval	Wide dosage variation; marginal liver benefit; no long-term MACE outcome data	[127,128]
Combined therapeutic regimens	GLP-1RA + SGLT2i	T2DM-complicated MASLD without severe infection	↓ major adverse liver outcomes	Most cohorts show ↓ MACE; one database shows mild MACE elevation	C	Preferred combination for T2DM/HF/CKD MASLD; GLP-1RA monotherapy first for isolated MASLD	Non-randomized emulation studies; median 6-month follow-up; conflicting cardiovascular risk results across databases monotherapy	[134-136]
	Resmetirom + GLP-1RA/SGLT2i	Biopsy-confirmed F2-F3 T2DM MASH	Higher MASH resolution with weight loss	No dedicated cardiovascular hard endpoint data	B	First-line combined regimen for biopsy-proven F2-F3 diabetic fibrosis; no drug antagonism signals	Derived only from phase III post-hoc subgroup analysis; small sample; unknown long-term combination safety	[137]
	Efruxifermin + GLP-1RA	Stable GLP-1RA-treated T2DM F1-F3 MASH	Extra hepatic fat reduction vs GLP-1RA monotherapy	No cardiovascular hard endpoint data	B	Exploratory add-on for residual steatosis/fibrosis; not applicable to F4 cirrhosis	Tiny phase IIb cohort (n = 31); only 12-week treatment; no large confirmatory trials	[138]
Preclinical/basic research	Engineered hepatocyte-derived EVs	Murine animal models only	Attenuate steatosis, MASH and fibrosis in mice	No human cardiovascular data	E	Pure basic research; no clinical translation plan	Only rodent data; unresolved mass production and targeting barriers; unknown human safety/efficacy	[107]
	GDF15	Animal experiments + human tissue detection	Markedly relieve MASH pathological phenotype	No human cardiovascular trial evidence	E	Exploratory molecular target only; no approved clinical formulation	Predicted appetite-suppressing side effects; long-term human safety unvalidated	[116]
	CHIP-targeted interventions	Population observational research only	Correlated with higher MASH/fibrosis risk	Correlated with elevated atherosclerotic burden	E	Only used as risk biomarker reference; no interventional drugs	Pure observational correlation, causal link unproven; no liver-specific CHIP therapies	[133]

Evidence Grading Criteria (a modified system combining the traditional evidence pyramid with GRADE downgrading logic): Grade A: ≥ 1 large, well-powered randomized controlled trial; pooled meta-analysis of homogeneous randomized controlled trials; or population-wide multi-cohort meta-analysis based on hard clinical endpoints; grade B: Single-center phase II/III randomized controlled trial employing surrogate endpoints or limited hard endpoints; or large prospective observational cohort study with adequate adjustment for confounders; grade C: Retrospective database emulation studies; case-control studies; post-hoc subgroup analyses without pre-specified endpoints; presence of obvious residual confounding; grade D: Small single-center case series; expert consensus opinions without quantitative clinical data; grade E: Cellular or rodent animal studies only; no human clinical trial data available. MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; FLI: Fatty liver index; RCT: Randomized controlled trial; BMI: Body mass index; GI: Gastrointestinal; HOMA-IR: Homeostasis model assessment of insulin resistance; GLP-1RA: Glucagon-like peptide-1 receptor agonist; CVD: Cardiovascular disease; MACE: Major adverse cardiovascular events; SGLT2i: Sodium-glucose cotransporter 2 inhibitor; T2DM: Type 2 diabetes mellitus; HF: Heart failure; CKD: Chronic kidney disease; THR-β: Thyroid hormone receptor-β; LDL-C: Low-density lipoprotein cholesterol; CVOT: Cardiovascular outcome trial; DILI: Drug-induced liver injury; LVEF: Left ventricular ejection fraction; ALT: Alanine aminotransferase; PPAR-γ: Peroxisome proliferator-activated receptor-γ; NAS: Nonalcoholic fatty liver disease activity score; MI: Myocardial infarction; RAAS: Renin-angiotensin-aldosterone system; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; PCSK9: Proprotein convertase subtilisin/kexin type 9; ASCVD: Atherosclerotic cardiovascular disease; FIB-4: Fibrosis-4; SAF-A: Steatosis-activity-fibrosis activity score; FGF21: Fibroblast growth factor 21; CCR2/CCR5: C-C chemokine receptor type 2/type 5; FXR: Farnesoid X receptor; OCA: Obeticholic acid; HDL-C: High-density lipoprotein cholesterol; ALP: Alkaline phosphatase; FGF19: Fibroblast growth factor 19; PNPLA3: Patatin-like phospholipase domain-containing protein 3; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction; HSD17β13: Hydroxysteroid 17-beta dehydrogenase 13; IL-1β: Interleukin-1β; hs-CRP: High-sensitivity C-reactive protein; AST: Aspartate aminotransferase; SBP: Systolic blood pressure; GDF15: Growth differentiation factor 15; CHIP: Clonal hematopoiesis of indeterminate potential; mAb: Monoclonal antibody.

CONCLUSION

As a systemic cardiometabolic disorder, MASLD involves complex interactive mechanisms among multiple human organs. Consequently, the clinical management of MASLD is gradually shifting from a traditional organ-centric model toward an integrated cardio-hepatic-metabolic framework. However, it remains unclear whether the association between MASLD and cardiovascular events reflects a direct causal relationship or is driven by shared underlying metabolic risk factors. Residual confounding cannot be completely excluded in the currently available evidence, and whether liver fibrosis itself directly drives CVD progression remains uncertain. This clinical uncertainty suggests that FIB-4 and VCTE should be used as complementary tools for cardiovascular risk assessment rather than as direct replacements for traditional risk factor stratification approaches.

Previous clinical studies focusing on the heart-liver connection have largely focused on histological improvement in a single organ system, or have only incorporated cardiovascular events as secondary or exploratory study endpoints. To date, no prospective clinical study has demonstrated that histological improvement serves as a valid surrogate endpoint for CVD risk reduction. The cardiovascular benefits of newly approved anti-MASH therapeutic agents also await further clinical validation. In addition, emerging research directions such as EV-mediated signaling, immunometabolic reprogramming, CHIP, and epigenetic modifications hold considerable research promise, but their translational clinical significance requires further systematic validation. Future research on the cardio-hepatic axis should focus on conducting large-scale prospective cohort studies to clarify the direct causality vs residual confounding debate; validating and optimizing the existing risk stratification framework across diverse patient populations; and conducting CVOTs for MASLD-directed therapeutic interventions. At the same time, multi-omics techniques, systems biology, and artificial intelligence tools should be fully leveraged to build precision prediction models, and a complete multidisciplinary collaborative framework encompassing hepatology, cardiology, endocrinology, and metabolic medicine should be established.