Decoding the Liver-Heart Axis in Cardiometabolic Diseases

Abstract

The liver and heart are closely interconnected organs, and their bidirectional interaction plays a central role in cardiometabolic disease. In this review, we summarize current evidence linking liver dysfunction – particularly metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and cirrhosis – with increased risk of heart failure (HF), and other cardiovascular disease. We discuss how these liver conditions contribute to cardiac remodeling, systemic inflammation, and hemodynamic stress, and how cardiac dysfunction in turn impairs liver perfusion and promotes hepatic injury. Particular attention is given to the molecular mediators of liver–heart communication, including hepatokines and cardiokines, as well as the emerging role of advanced research methodologies – including omics integration, proximity labeling, and organ-on-chip platforms – that are redefining our understanding of interorgan crosstalk. By integrating mechanistic insights with translational tools, this review aims to support the development of multi-organ therapeutic strategies for cardiometabolic disease.

1. Introduction

Cardiovascular diseases (CVD) are the leading global cause of death, driven by complex and multifactorial pathophysiology¹. Among the contributors to CVD progression, the liver has gained attention as a key player through its complex interplay with the heart. Liver dysfunction has long been considered as separate or secondary to cardiac disease, but growing evidence challenges this view. For example, metabolic dysfunction-associated steatotic liver disease (MASLD), affecting more than 30% of adults², increases cardiovascular event (CVE) risk two- to threefold³, making CVD the primary cause of death in these patients. Notably, MASLD often precedes CVD, and this risk persists even after adjusting for concurrent comorbidities^3,4. Similarly, alcohol related liver disease (ALD) and later stages of hepatopathy, such as liver cirrhosis, significantly impact on the cardiovascular system. Detrimental effects of liver disease on cardiac function often converge into heart failure (HF), which, at once, may drive congestive hepatopathy and/or liver ischemia in patients with severely compromised cardiac output.

The liver-heart axis involves metabolic, inflammatory, and hemodynamic pathways, with interactions forming a vicious cycle where both organs contribute to disease progression. The majority of these pathways are still under investigation, with a growing body of evidence revealing unexpected mechanisms. Recently, circadian misalignment has been recognized to exacerbate this crosstalk, increasing risk of CVD^5–8. Disruptions in liver circadian rhythms impair glucose metabolism and lipid regulation, while cardiac circadian dysfunction predisposes individuals to hypertension and increased susceptibility to ischemic heart disease (IHD)⁹.

Investigating liver-heart interactions is complex, requiring advanced research methodologies to validate clinical findings in experimental models. In this review we will examine recent evidence on the liver-heart crosstalk and its impact on CVD. Cutting-edge research techniques for liver-heart crosstalk investigation will be described, moving from multi-organ disease animal models to systems biology approaches, organ-on-a chip and proximity labelling for interorgan signalling. Therapeutic strategies holding promise to break the liver-heart pathological interaction will be described. By integrating current knowledge with innovative research strategies, we aim to equip scientists with tools to explore this axis and uncover its contribution to CVD.

Physiological Crosstalk Between the Liver and Heart

A stable communication between heart and liver is key for systemic energetic and hemodynamic homeostasis (Figure 1). The liver coordinates blood concentration of glucose, fatty acids (FAs), ketone bodies (KBs) and amino acids. Metabolites produced in the liver are the main energy source for all organs, including the heart, the organ having the highest energy demand per gram of tissue^10,11. Metabolites supply from the liver to the heart is critical for cardiac energetics and is dynamic. During fasting, glucagon promotes hepatic glycogenolysis and gluconeogenesis, enabling glucose production from non-carbohydrate precursors such as lactate, glycerol, and amino acids¹². Simultaneously, low insulin levels and activation of the sympathetic nervous system (SNS) promote lipolysis in adipose tissue, releasing FAs into circulation that are subsequently oxidized in the liver and transformed in KBs to be used in the heart^13,14 (Figure 1). Also, during exercise, increased cardiac output (CO) is coordinated with enhanced hepatic gluconeogenesis and higher glucose uptake in skeletal muscles to sustain metabolic balance¹⁵. SNS activation¹⁶, cortisol release¹⁷ and Renin-Angiotensin-Aldosterone System (RAAS) modulation contribute to this highly coordinated liver-heart response¹⁸.

Figure 1 -. Physiological liver-heart interplay.

Liver metabolism, cardiac hemodynamic, Sympathetic Nervous System (SNS) and Circadian clocks work in parallel to coordinate liver-heart homeostatic balance.

BCAA - Branched Chain Amino Acids, FFAs - Free Fatty Acids, KBs – Ketone Bodies.

Conversely, the heart ensures both blood supply to and drainage from the liver, both of which are crucial for its proper function (Figure 1). The liver receives around 1200–1800 ml of blood per minute, representing ¼ of cardiac output and 80% of this volume reaches the organ via the portal vein, collecting blood from the splanchnic region, the body’s largest blood volume reservoir¹⁹. In basal conditions, the liver and splanchnic vessels serve as a preload reserve, rapidly mobilized to support increased CO. During exercise, stroke volume rises alongside vena cava blood flow. If intrahepatic resistance increases, preload failure may occur, impairing blood return to the heart and limiting exercise capacity.

The liver is also central to lipoprotein metabolism, which facilitates the transport and distribution of lipids throughout the body. The liver synthesizes and secretes very low-density lipoproteins (VLDLs), which deliver triglycerides and cholesterol to peripheral tissues²⁰. The liver also prevents lipid accumulation from the bloodstream via chylomicron and lipoprotein receptor-mediated endocytosis and regulating reverse cholesterol transport by high-density lipoprotein (HDL) metabolism. Genetic and non-communicable diseases affecting lipoprotein metabolism in the liver directly promote CVD, as well described in clinical and preclinical settings^21–24.

The liver serves as the primary organ for protein metabolism²⁵, maintaining nitrogen balance (e.g. via urea cycle) and systemic homeostasis. It synthesizes most plasma proteins, including albumin, which regulates oncotic pressure and facilitates the transport of hormones, drugs (including loop diuretics), and FAs. Additionally, the liver produces essential clotting factors necessary for haemostasis²⁶. Many are the cardiovascular detrimental effects of deranged protein metabolism in the liver. Altered amino acid metabolism and urea cycle correlate with metabolic dysfunction (e.g. insulin resistance – IR²⁷) atherosclerotic cardiovascular disease (ASCVD)^28,29, and HF^30,31. Low oncotic pressure promotes extracellular fluid accumulation and thus systemic congestion (worsening HF symptoms). Altered coagulation profile, on one hand drives thromboembolic events, on the other hand prolongs clotting time, interacting with antithrombotic therapies. On both sides, thrombotic and haemorrhagic imbalances correlate liver function and CVE. Moreover, several cardiovascular drugs (including direct oral anticoagulants – DOACs, antiarrhythmic drugs, and antiplatelet agents – e.g. clopidogrel) are metabolized in the liver, further entangling, in both a mechanistic and clinical perspective, CVD progression and compromised liver function.

In summary, cardiac and liver functions are highly coordinated. Disruptions in liver-heart axis potentially affect cardiac energetics, exercise capacity, fluid balance, atherosclerotic plaque formation, coagulation profile, and drug metabolism delineating the broad perimeter of liver-heart interaction in CVD.

2. Liver diseases affecting cardiovascular system

MASLD: a key accelerator of cardiometabolic syndromes

Disruptions in liver-heart crosstalk contribute to the pathogenesis of a number of CVD, but the subgroup of cardiometabolic disorders are of particular interest and concern. Cardiometabolic diseases are interrelated disorders including obesity, T2D, dyslipidemia and hypertension, which frequently coexist and synergistically drive CVD such as IHD, cerebrovascular disease, and HF. Cardiometabolic disease are a massive threat to global health. Almost half of the adults aged 25 or older are living with obesity³² and T2D affects more than 500 million people worldwide, a prevalence expected to double by 2050³³. In 2021, 3.71 million deaths were attributable to overweight and obesity³⁴ and most of these deaths were due to CVD.

MASLD is a highly prevalent cardiometabolic disease, affecting more than 30% of adults globally³⁵, with a prevalence rising to 55–70% in patients with T2D^36–38 and 70–75% in overweight or obese individuals ³⁹. MASLD is defined by the presence of steatotic liver disease (SLD, defined as ≥5% liver fat content confirmed by imaging, biopsy, or biomarker-based assessment) in combination with at least one out of five features of metabolic syndrome (overweight or obesity, dysglycaemia or T2D, high plasma triglycerides, low HDL cholesterol, hypertension) and no other discernible cause for SLD². The spectrum of MALSD span from milder forms with little or no inflammation to metabolic dysfunction-associated steatohepatitis (MASH), further progressing to liver fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC) in most severe cases²(Figure 2). Progression to cirrhosis is observed in 20% of MASLD patients, with fibrosis severity serving as a key predictor of adverse liver related events⁴⁰. Additionally, T2D further elevates the risk of hepatic decompensation and HCC in these individuals⁴¹. Considering the rising prevalence in obesity and T2D, the number of MASLD related HCC and liver transplants is expected to double and quadruple respectively by 2050 in the US⁴².

Figure 2 – Mechanisms of pathological liver-heart interaction.

Liver steatosis, alcohol consumption and congestive hepatopathy synergistically promote liver inflammation and fibrosis, eventually leading to cirrhosis and HCC. Liver disease and cardiovascular events are entangled in a pathophysiological crosstalk including hemodynamics and signaling molecules.

ASCVD - Atherosclerotic Cardiovascular Disease, BNP – Brain Natriuretic Peptide, FGF21 - Fibroblast Growth Factor 21, FSTL1 - Follistatin-Like 1, FXI – Factor XI, GDF15 - Growth Differentiation Factor-15, HCC – Hepatocellular Carcinoma, HFpEF - Heart Failure with preserved Ejection Fraction, HFrEF – Heart Failure with reduced Ejection Fraction, IHD – Ischemic Heart Disease, MG53 - Mitsugumin 53, POSTN – Periostin, SAA1/A - Serum Amyloid A Proteins 1 And 4, sPLA2 – Soluble Phospholipase A.

Increase in liver-related events, however, is not the major threat in MASLD. Subjects with MASLD have significant higher risk of CVE^43,44, with CVD representing the leading cause of morbidity and mortality in these patients^45–47. Robust epidemiological data indicate MASLD contribution to increased risk of CVD to be independent of coexisting risk factors in affected patients⁴⁸. A retrospective study including over 111,000 patients, further revealed that MASLD was associated with a 1.54 times higher incidence of acute myocardial infarction (AMI), independently of other risk factors⁴⁹.

MASLD is specifically correlated to one HF phenotype, namely heart failure with preserve ejection fraction (HFpEF)⁵⁰. MASLD is present in up to 50% of HFpEF patients, with advanced liver fibrosis found in 8–38%, and cirrhosis in 7–12%^51–53. MASLD correlates with several aspects of diastolic dysfunction^54,55. This correlation is independent of age, sex, obesity, hypertension, and T2D ^{48,50,54–62}. Consistently, advanced MASLD stages, particularly those with hepatic fibrosis, predicts worse HF outcomes and cardiovascular mortality^52,63,64.

Importantly, lean patients with MASLD, despite favorable metabolic profiles, still face an increased risk of CVE⁶⁵ - partly due to cardiac remodeling and LV diastolic dysfunction ^66,67. This supports the view that MASLD contributes to CVD risk independently of common metabolic factors.

MASLD is also intricately tied to atherogenic dyslipidaemia and hypertension, both of which amplify CVD risk through interconnected metabolic and inflammatory pathways⁶⁸. A recent meta-analysis involving Western and Asian cohorts demonstrated that MASLD is associated with increased carotid intima-media thickness (OR 2.00, 95% CI: 1.56–2.56) and a higher prevalence of coronary artery calcification (OR 1.21, 95% CI: 1.12–1.32)⁶⁹. Notably, this association persists in individuals with severe coronary artery calcifications⁶⁹.

However, despite MASLD’s strong association with increased ASCVD, this risk does not appear to independently translate into increased ASCVD mortality after accounting for traditional cardiovascular risk factors^70,71. Some evidence suggests that advanced MASLD stages, particularly those with higher fibrosis scores, may pose a greater risk for CVE⁷². However, a prospective study involving biopsy-confirmed MASLD patients found no apparent difference in cardiac event rates based on fibrosis stages⁴⁰.

Pathophysiological underpinnings connecting MASLD and CVD

A complex pathophysiology links MASLD to the progression of CVD disease. IR is a key driver linking MASLD to both HFpEF and ASCVD. In adipose tissue, IR prevents insulin-mediated suppression of postprandial lipolysis, increasing circulating FAs and their delivery to the liver. Concurrently, hepatic IR enhances de novo lipogenesis and impairs mitochondrial fatty acid oxidation, promoting steatosis. It also stimulates gluconeogenesis—normally suppressed by insulin—leading to hyperglycaemia. Elevated glucose contributes to endothelial dysfunction and oxidative stress, while also promoting the formation of advanced glycation end-products (AGEs), which crosslink myocardial collagen and impair diastolic compliance, a hallmark of HFpEF^73,74.

Liver steatosis in MASLD further aggravates systemic IR by releasing inflammatory cytokines (e.g., FGF21, fetuin-A, fetuin-B), disrupting insulin signaling in skeletal muscle, adipose tissue, and pancreas⁷⁵. This self-reinforcing loop exacerbates glucose intolerance and CVD progression. A 2012 meta-analysis of >500,000 individuals showed a 1.46-fold increase in ASCVD risk per one standard deviation increase in HOMA-IR⁷⁶. HOMA-IR is also independently associated with impaired LV relaxation, with diastolic dysfunction affecting up to 50% of T2D patients^77–79. IR disrupts endothelial insulin signaling, suppressing the PI3K/Akt/eNOS pathway⁸⁰ while overactivating the MAPK pathway, leading to vasoconstriction, inflammation, and atherosclerosis^81,82. In cardiomyocytes, IR promotes sarcolemmal translocation of CD36 and internalization of GLUT4, increasing lipid uptake and intracellular lipid accumulation. This lipotoxicity contributes to HFpEF pathogenesis^74,83,84.

MASLD is also characterized by atherogenic dyslipidemia—elevated triglycerides, reduced HDL-C, and increased small dense LDL particles. Hepatic IR alone is sufficient to induce this profile in murine models⁸⁵. Elevated FAs and triglycerides also drive ectopic lipid deposition in the myocardium, worsening diastolic dysfunction^86,87. Furthermore, MASLD promotes a prothrombotic state via increased coagulation factors, reduced fibrinolysis, platelet hyperactivity, and endothelial dysfunction^88–91, increasing the risk of acute myocardial infarction, stroke, and peripheral artery disease⁹². Hepatokines such as FGF21 and ANGPTLs further mediate liver–heart communication and cardiac remodeling^93–95(Figure 2).

These findings underscore the complex and multifaceted relationship between MASLD and CVD. While MASLD clearly elevates the risk of various CVE, the extent to which it independently influences cardiovascular mortality remains an area requiring further investigation, particularly in relation to disease severity, fibrosis stage, and underlying metabolic dysfunctions such as IR.

Alcoholic Liver Disease and CVD

Chronic alcohol consumption is a major risk factor for liver disease, with significant downstream effects on cardiovascular health. Alcohol-associated liver disease (ALD) encompasses a spectrum of liver injury ranging from hepatic steatosis to alcohol-associated hepatitis, cirrhosis, and acute-on-chronic liver failure⁹⁶(Figure 2). Disease progression depends on factors such as heavy drinking, sex, genetic predisposition, diet, ethnicity, and comorbidities⁹⁶. A recent Delphi consensus introduced the term metabolic dysfunction-associated ALD (MetALD)⁹⁷ to describe individuals with MASLD who also consume excess alcohol. MetALD is associated with more severe hepatic fibrosis than MASLD, suggesting a synergistic effect of alcohol on disease progression⁹⁸ (Figure 2).

A systematic review of 50,302 ALD patients reported a 40% increase in CVD-related mortality in those with alcohol-associated steatosis, rising to a fivefold increase in alcohol-associated hepatitis and 2.5-fold in cirrhosis⁹⁹. In a Swedish cohort of 3,488 individuals with ALD, CVD risk doubled in the first year post-diagnosis, with a five-year cumulative incidence of 12% versus 6% in controls¹⁰⁰. This risk remained modestly elevated even 10 years post-diagnosis. NHANES III data from 7,980 participants revealed higher all-cause and cardiovascular mortality in individuals with MetALD and ALD with metabolic dysfunction than in those with MASLD or non-MASLD steatosis¹⁰¹. A Korean study of 105,328 individuals found ALD was more strongly associated with coronary artery calcium (CAC)—a marker of subclinical atherosclerosis—than MASLD, while excessive alcohol consumption alone was also linked to increased CAC, albeit less than ALD or MASLD¹⁰². In a large Korean cohort (n = 165,654), the presence of MASLD conferred a 19% higher CVE risk compared to the general population. This increased to 28% and 29% in MetALD and ALD patients, respectively¹⁰³. These associations were consistent across BMI categories and stages of liver disease, suggesting shared pathophysiological mechanisms such as systemic inflammation and metabolic dysfunction¹⁰².

Ethanol metabolism generates the toxic metabolite acetaldehyde via alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). Acetaldehyde accumulation is exacerbated by impaired detoxification via aldehyde dehydrogenase (ALDH), primarily ALDH2. Ethanol and acetaldehyde disrupt hepatic lipid metabolism by promoting de novo lipogenesis and suppressing fatty acid oxidation, rapidly inducing steatosis. Acetaldehyde also directly impairs cardiac myocyte contractility. At the cellular level, acetaldehyde activates protein kinase C (PKC) and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) in hepatic stellate cells, stimulating type I collagen synthesis and fibrogenesis. Chronic alcohol exposure shifts metabolism toward CYP2E1, increasing reactive oxygen species (ROS) and hydroxyethyl radicals. These promote lipid peroxidation and oxidative stress—key drivers of ALD. ROS further trigger pro-inflammatory cytokine release^104,105, including tumour necrosis factor-alpha (TNF-α) interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and high mobility group box 1 (HMGB1)^106,107, exacerbating hepatic inflammation and systemic cardiovascular risk. ALD is associated with insulin resistance and dyslipidemia—two major CVD risk factors. Chronic alcohol intake increases visceral fat accumulation and alters lipid profiles, contributing to atherosclerosis and heightened cardiovascular morbidity⁹⁹.

In summary, the interplay between ALD and CVD is multifactorial, involving metabolic dysfunction, oxidative stress, inflammation, and direct cardiotoxicity. These findings underscore the need for integrated approaches to prevent and manage cardiovascular complications in ALD.

Cirrhosis and Cirrhotic Cardiomyopathy

Cirrhosis, the common final stage of severe liver disease, is characterized by a complete derangement of hepatic architecture, promoted by formation of regenerative nodules encased by fibrous bands as a reaction to chronic liver damage, ultimately resulting in portal hypertension, liver failure¹⁰⁸, and extra-hepatic complications.

Cardiometabolic consequences of cirrhosis include impaired glucose metabolism (hyperglycaemia due to reduced catabolism of glucagon and growth hormone) and increased IR, followed, in later stages, by hypoglycaemia due to decreased insulin catabolism and reduced gluconeogenesis/glycogenolysis¹⁰⁹, altered protein metabolism (hypoalbuminemia and ascites, loss of muscle proteins)¹¹⁰, and lipid metabolism (hypocholesterolemia¹¹¹ with alterations of cell membranes, and lipids malabsorption due to reduced bile acid synthesis¹¹².

Due to the continuous liver-heart interplay, a severe complication of cirrhosis is cirrhotic cardiomyopathy (CCM), a chronic clinical condition characterized by reduced myocardial contractile response to stress (physiological, pathological, or pharmacologic stress), diastolic dysfunction, and electrophysiological abnormalities¹¹³. CCM affects approximately 60% of patients with cirrhosis¹¹⁴. It arises from a combination of arterial vasodilation, central hypovolemia, hyperdynamic circulation, and portal hypertension, often accompanied by hepatorenal and hepatopulmonary syndromes^115–117. Portal hypertension induces splanchnic vasodilation via liver-derived vasodilators such as nitric oxide, carbon monoxide, and prostacyclin^118,119, reducing systemic vascular resistance and arterial pressure, and redistributing blood flow. Portosystemic shunting and bacterial translocation worsen hypovolemia, triggering sympathetic activation and leading to elevated heart rate and cardiac output^21,120. Despite this, cirrhotic patients show reduced cardiac output during physical stress, largely due to inadequate heart rate response and diminished myocardial contractility¹²¹. Chronic exposure to elevated noradrenaline in cirrhosis leads to internalization and downregulation of β-adrenergic receptors, impairing contractility¹²². Diastolic dysfunction is a hallmark of CCM, with prevalence ranging from 43% to 70%¹²³. It often precedes systolic impairment and may be evident even at rest. This dysfunction stems from increased myocardial wall stiffness, attributed to mild hypertrophy, fibrosis, subendothelial edema¹²⁴, and altered titin protein structure, as shown in cirrhotic rat models¹²⁵. QT-interval prolongation, caused by defective K+ channel function in ventricular cardiomyocytes, occurs in 30–60% patient with CCM¹²⁶ and might help identify cirrhotic patients at risk of CCM.

No specific treatments are available for CCM. However, in addition to diuretics, non-selective betablockers can help reduce hyperdynamic load and improve QT interval¹²⁷. Angiotensin-converting enzyme (ACE) inhibitors should be used with caution in patients with CCM, as they may worsen renal function and exacerbate the existing vasodilation associated with advanced cirrhosis¹¹⁶.

3. Major CVD driving liver disease

The spectrum of CVD affecting liver function largely converges in HF, representing an intermediate or advanced stage occurring in the progression of many cardiac diseases ¹²⁸. HF affects 1–2% of the global population and impose a significant burden of morbidity and mortality¹²⁹. Several HF groups and phenotypes exists, each characterized by distinct aetiologies and pathophysiology.

The best studied form of HF is heart failure with reduced ejection fraction (HFrEF), in which LV ejection fraction (LVEF) – the most commonly adopted indicator of LV systolic function – is ≤40% at rest, thus significantly impaired¹³⁰(Figure 2). Irrespectively from the etiology, HFrEF ultimately converge toward a similar pathophysiological pattern and clinical progression. Key mechanisms – such as altered sympathetic nervous system (SNS) activity, secondary hyperaldosteronism, and fluid retention – overlap with those seen in cirrhosis. As a result, some therapeutic approaches are shared between the two conditions, including the use of mineralocorticoid receptor antagonists (MRAs) and beta-blockers.

HFpEF – HF with LVEF ≥50% – accounts for more than 50% of total HF cases and its prevalence is expected to soon surpass HFrEF^131,132. HFpEF is syndrome with heterogeneous phenotypes, each characterized by distinct pathophysiology. Among the different HFpEF phenotypes, the cardiometabolic one, is driven by metabolic syndrome. Cardiometabolic HFpEF, is arguably the most common HFpEF phenotype, since approximately 80% of HFpEF patients are overweight or obese^133,134 and metabolic comorbidities such as T2D and dyslipidaemia are highly prevalent in these patients^135–137. Cardiometabolic HFpEF is associated with worse quality of life and high cardiovascular mortality^138,139. Mechanistically, this phenotype is linked to lipid accumulation in the heart (defined as myocardial steatosis^86,140–142) and systemic inflammation, making it a form of organ damage related to metabolic dysfunction, similar to MASLD¹⁴³.

In subjects living with obesity and metabolic syndrome, excess lipids from adipose tissue accumulate in the heart, promoting diastolic dysfunction, LV hypertrophy, and reduced exercise capacity^{86,140,141,144}. Mechanisms include fibrosis, microvascular dysfunction, and impaired mitochondrial energy metabolism, limiting ATP availability for cardiac relaxation and reducing cardiac output during exertion^145–150 Changes in cardiac metabolism are key in HF pathogenesis. In HFrEF, metabolic flexibility is impaired and FAs and glucose oxidation are reduced¹⁵¹. Increased oxidation of β-hydroxybutyrate (β-OHB), the primary KB, is observed in HFrEF^152–154, with elevated circulating β-OHB levels been consistently reported in both animal models and humans, suggesting that HFrEF stimulates endogenous ketogenesis^152,155,156. Ketogenesis occurs primarily in the liver, which therefore is pivotal to sustain cardiac energetics in these patients. The mechanisms driving increased hepatic ketogenesis in HFrEF remain poorly understood. Reduced cardiac utilization of long-chain FAs may shifts their systemic metabolism toward hepatic β-oxidation, thereby fuelling ketogenesis. Additionally, HF is associated with increased natriuretic peptide concentrations, heightened sympathetic tone and elevated catecholamine levels, all of which promote adipose tissue lipolysis and increase circulating FAs^157–159. At least in the short term, the shift toward KBs is an adaptive mechanism of the disease^160,161. Importantly, impaired ketogenesis has been described in MASLD, especially when β-OHB levels are measured after prolonged fasting^162,163, with lower ketogenic capacity in patients with advanced disease stages^164,165. Whether the coexistence of impaired ketogenesis in patients with MASLD contribute to worse cardiac energetics in HFrEF is unknown. Importantly, if in HFrEF KBs serve as alternative energy source, KB utilization in HFpEF remains less defined. As observed in different animal models, KB oxidation is unchanged/reduced in HFpEF animals compared with non-failing controls, with reduced expression of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme for KB oxidation^145–147. The role of impaired liver ketogenesis in HFrEF vs HFpEF patients remains largely unexplored.

Heart-liver hemodynamic interactions in HF: congestive hepatopathy (CH)

Congestive hepatopathy (CH), or cardiac hepatopathy, affects 20–30% of HF patients and is a direct result of elevated central venous pressure (CVP), particularly in right heart failure (RHF)¹⁶⁶, although CH can also arise in constrictive pericarditis and severe tricuspid regurgitation (TR). Chronic hepatic congestion from CVP elevation may lead to fibrosis, cirrhosis, or hepatocellular carcinoma.

CH originates from impaired hepatic blood outflow. Hepatic sinusoids receive blood from both the portal vein and hepatic artery, draining into hepatic veins and ultimately the inferior vena cava. As hepatic veins lack valves, increased right atrial pressure is directly transmitted into the liver, impeding portal inflow and hepatic perfusion. The hepatic artery buffer response can partially compensate by increasing arterial inflow but cannot prevent congestion-induced injury. Sinusoidal dilation, perisinusoidal edema, and oxygen diffusion impairment disrupt hepatocyte metabolism and promote fibrogenesis, giving rise to the mottled “nutmeg liver” appearance¹⁶⁷. Compression of bile canaliculi may impair bile acid secretion and drug metabolism199. Elevated sinusoidal pressure triggers shear stress, activating hepatic stellate cells and suppressing endothelial nitric oxide (NO) production, further promoting fibrosis^168,169. Inflammation, oxidative stress, and neurohormonal dysregulation seen in HF exacerbate liver damage.

RHF contributes to both HF phenotypes via distinct pathways. In HFpEF, LV diastolic dysfunction elevates left atrial pressure, increasing pulmonary pressures and leading to pulmonary hypertension and RV dysfunction—seen in 20–35% of HFpEF patients¹⁷⁰. This culminates in CH, which often coexists with MASLD, amplifying disease severity. In HFrEF, impaired LV contractility reduces CO, raising left-sided filling pressures and causing secondary pulmonary hypertension¹⁷¹. RV compensation may ultimately fail, resulting in RHF and CH¹⁷².

CH often remains clinically silent, overshadowed by HF symptoms. When evident, symptoms include hepatomegaly, right upper quadrant discomfort, jaundice, ascites, nausea, vomiting, and peripheral edema¹⁷³. Management prioritizes cardiac optimization and decongestion. Loop diuretics are first line choice of treatment but require careful monitoring to avoid hepatorenal syndrome. Sodium restriction, paracentesis, and adjunctive therapies may be necessary in refractory ascites^174,175.

TR, even without overt HF, can cause hepatic congestion and fibrosis. Severe TR leads to retrograde flow and CVP elevation, transmitted to hepatic veins. In a study of 435 TR patients, 14.5% had liver disease; elevated liver enzymes were common¹⁷⁶. Another cohort found liver disease in 11% of isolated TR cases¹⁷⁷. Liver stiffness, measured via transient elastography, independently predicts outcomes in TR patients¹⁷⁸, emphasizing the need to assess hepatic involvement, even absent HF.

Acute Heart Failure and Liver Injury

Acute heart failure (AHF), ranging from ADHF to cardiogenic shock, presents with rapid HF decompensation. Hepatic dysfunction affects 20–30% of AHF patients¹⁶⁶. Acute cardiogenic liver injury (ACLI), or ischemic hepatitis, results from abrupt reductions in CO, impairing hepatic oxygenation and metabolism¹⁷⁹. ACLI manifests as sudden hepatocellular injury, elevated aminotransferases (>20× upper limit of normal), and in severe cases, acute liver failure^180,181. Histologically, ACLI is characterized by centrilobular (zone 3) hepatocyte necrosis, as these cells are most susceptible to hypoxia. Pre-existing hepatic congestion intensifies the risk of ACLI, as reduced CO further impairs compensatory mechanisms. Diagnosis of ACLI relies on clinical context—HF, circulatory collapse, or respiratory failure—and exclusion of other hepatic insults. Treatment targets underlying AHF. Although liver enzyme levels may normalize within 3–7 days in survivors, ACLI carries a high in-hospital mortality risk¹⁸¹.

Cardiac Amyloidosis and Hepatic Involvement

Cardiac amyloidosis, particularly transthyretin (ATTR) amyloidosis, is characterized by the deposition of amyloid fibrils in the myocardium, leading to restrictive cardiomyopathy¹⁸². This condition can also affect the liver, either directly through amyloid deposition or indirectly via cardiac dysfunction. Liver involvement is evidenced by elevated liver stiffness, which correlate with the severity of cardiac amyloidosis. In a cohort of patients with wild-type ATTR cardiac amyloidosis, higher liver stiffness was associated with advanced disease stages and higher mortality¹⁸³. Furthermore, elevated liver enzymes, particularly alkaline phosphatase and transaminases, have been observed in patients with cardiac amyloidosis, indicating hepatic dysfunction¹⁸⁴. Altered transient elastography due to either CH or deposition of amyloid has been observed also in patients with light chain amyloidosis¹⁸⁵, suggesting that increased liver stiffness may have several explanations in these patients. These findings highlight the importance of monitoring liver function in patients with cardiac amyloidosis, as hepatic involvement can have prognostic implications and may influence therapeutic strategies.

4. Mediators of Bidirectional Crosstalk Between Liver and Heart

Communication between the liver and heart extends far beyond hemodynamic and metabolic fluxes. These two organs are interconnected through a complex network of signals that play roles in both liver and heart diseases. Decoding hepatokines and cardiokines is essential for understanding the mechanisms underlying interorgan disease progression. Notably, many liver and heart functions – especially metabolic ones – are coordinated in a time-dependent manner via circadian clocks. This recently uncovered mode of communication has been shown to significantly impact cardiometabolic health and holds promise for identifying new therapeutic targets.

Liver to Heart communication

Hepatokines, liver-derived secreted proteins, are critical mediators linking hepatic metabolism to whole-body homeostasis, particularly in cardiometabolic diseases. Among hepatokines, Coagulation factor XI (FXI), FGF21, and serum amyloid A proteins (SAA1/4) have garnered attention for their roles in cardiac metabolism and remodelling (Figure 2).

FXI has been traditionally known as a coagulation factor, but recently has been implicated in cardiovascular pathology. Elevated FXI levels are associated with thrombo-inflammation, driving endothelial dysfunction and cardiac fibrosis^186–188. Pro-thrombotic states exacerbate CVD by promoting microvascular injury, platelet activation, and chronic inflammation. Excess FXI activity can also amplify coagulation cascade crosstalk with pro-fibrotic pathways, worsening cardiac remodelling seen in HF. Interestingly, FXI may play a context-dependent cardioprotective role under specific conditions^189,190. For example, in a preclinical model of HFpEF, FXI overexpression during disease progression surprisingly demonstrated cardioprotective effects. This finding highlights the nuanced role of FXI, where modest levels may stabilize microvascular integrity and endothelial repair, mitigating inflammation and fibrosis. Understanding the threshold at which FXI transitions from protective to pathological remains a key research focus.

FGF21 is a well-established hepatokine that improves metabolic homeostasis under nutrient stress^191–193. It functions as a systemic mediator of energy balance, enhancing glucose uptake, FA oxidation, and mitochondrial function in peripheral tissues, including the heart^194–196. Elevated FGF21 levels are observed during metabolic stress, serving as a compensatory response to obesity, IR, and lipotoxicity. In cardiometabolic diseases, FGF21 has potent cardioprotective effects by alleviating lipotoxicity injury and improving myocardial energy efficiency^197,198. FGF21 reduces cardiac hypertrophy and fibrosis by activating AMPK and PGC1a signalling, which enhances mitochondrial biogenesis and reduces oxidative stress.

Serum amyloid proteins (SAA1/4) are acute-phase hepatokines primarily induced under inflammatory states^199,200. While essential for host defence, chronically elevated SAA1/4 levels in metabolic syndrome can exacerbate cardiac pathology. SAAs promote systemic inflammation, activate immune cells, and induce extracellular matrix (ECM) deposition, contributing to cardiac hypertrophy and fibrosis^201–203. In the heart, SAA1/4 abundance associates with an enhanced pro-inflammatory state and fibrotic gene programs^201,203,204, likely contributing to maladaptive cardiac remodelling, although the direct evidence of these heart or resident cell-specific effects is lacking. Elevated SAA1/4 levels in obese or insulin-resistance individuals reflect a persistent hepatic inflammatory state that perpetuates cardiovascular dysfunction^199,203,205.

Hepatokines such as FXI, FGF21, and SAA1/4 exemplify the liver’s critical role in regulating cardiac remodelling and metabolism. FXI’s dual nature underscores the need for context-dependent therapies to modulate its levels safely. Meanwhile, FGF21 emerges as a protective hepatokine, linking metabolic state to cardiomyocyte health, and SAA1/4 highlights the detrimental impact of chronic inflammation on cardiovascular health. Targeting these hepatokines, particularly through interventions via behavioural and/or pharmacological modulation, holds promise for treating the liver-heart axis in cardiometabolic syndrome and preventing CVD progression.

In addition to hepatokines, liver-derived extracellular vesicles (EVs) are increasingly recognized as mediators of hepatic metabolic dysfunction in CVD. MASLD leads to an increased release of EVs enriched in proinflammatory factors²⁰⁶, which may propagate systemic inflammatory signalling and reinforce the chronic low-grade inflammation underlying both ASCVD and HF. Steatotic hepatocyte-derived EVs also promote endothelial dysfunction by increasing coronary microvascular permeability and inflammation^207,208. Additionally, liver-secreted EVs contribute to the development of metabolic cardiomyopathy by impairing cardiomyocyte mitochondrial function²⁰⁹. While the study of liver-derived EVs in CVD is promising, this area remains relatively novel, and further research is needed to establish clear connections and develop therapeutic strategies.

Heart to liver communication

Growing evidence supports the idea that the heart may influence systemic metabolism, including hepatic metabolism, by functioning as an endocrine organ (Figure 2). A key example of heart-secreted proteins involved in regulating whole-body energetics are the natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). While natriuretic peptides are best known for their role in adipose tissue, where they promote lipolysis and increase energy expenditure^210–212, their receptor, NPR-A, is also expressed in the liver²¹³. Infusion of ANP in healthy individuals increases circulating levels of FAs and of β-OHB²¹⁴. Accordingly, a covariant structure analysis identified a positive correlation among plasma levels of KB and BNP in cohort of patients with cardiovascular disorders²¹⁵. In a model of diet-induced obesity, ANP administration significantly reduced hepatomegaly and hepatic steatosis, suggesting a direct role for natriuretic peptides in regulating liver metabolism. ANP has also been shown to modulate hepatic carbohydrate metabolism by inhibiting pyruvate kinase activity²¹⁶.

Beyond natriuretic peptides, cardiac cells secrete a variety of proteins and peptides, collectively referred to as cardiokines (Figure 2). For instance, cardiac fibroblasts and cardiomyocytes secrete immunomodulatory signals in pathological conditions^217,218. Although the link between myocardial inflammation and liver dysfunction remains unclear, a recent study demonstrated that myocardial ischemia and AMI in particular exacerbates liver damage in MASLD through two mechanisms: (1) increasing inflammatory monocyte levels and their recruitment to the liver, and (2) secreting periostin (POSTN), an extracellular matrix protein re-expressed by cardiac fibroblasts during cardiac injury²¹⁹. AMIs lead to elevated hepatic triglyceride levels, worsened steatosis, and aggravated fibrosis²²⁰. POSTN delivery to primary hepatocytes increased lipid accumulation by activating JNK1/2 signalling and reducing peroxisome proliferator-activated receptor α (PPARα) levels²²⁰. Another heart-liver axis in AMI involves interleukin-6 (IL-6) and hepatic STAT3 signalling. STAT3 activation suppresses the mineralocorticoid receptor and upregulates hepatic FGF21²²¹. Given the role of IL-6 in liver homeostasis, including regeneration, insulin signalling, and glucose metabolism²²², AMI-induced IL-6 release may contribute to additional hepatic alterations. Indeed, transcriptional analysis of metabolically active tissues during AMI progression revealed dysregulation of immune response and fatty acid metabolism pathways in the liver²²³.

Follistatin-like 1 (FSTL1), a glycoprotein secreted by cardiomyocytes and fibroblasts in response to pathological stimuli such as pressure overload and ischemia/reperfusion, also plays a role in systemic metabolism²²⁴. Elevated circulating FSTL1 levels are associated with poor prognosis in AMI^225–227. FSTL1 exerts cardioprotective effects by enhancing cardiomyocyte survival, reducing apoptosis, and modulating inflammation and energetics^224,228,229. Beyond its local actions, FSTL1 influences systemic metabolism by increasing FA oxidation and altering circulating levels of FAs, glucose, and KBs. Treatment of cardiomyocytes and myotubes with FSTL1 enhances AMPK phosphorylation and mitochondrial respiration²²⁹. While its hepatic effects remain unclear, muscle-derived FSTL1 has been implicated in MASH pathogenesis via a skeletal muscle-liver axis, and recombinant FSTL1 increases triglyceride accumulation in primary hepatocytes exposed to palmitic acid²³⁰.

Another example of heart-liver interaction involves secreted phospholipase A2 (sPLA2), an enzyme highly expressed in the heart that hydrolyses phospholipids to release FAs and lysophospholipids. sPLA2 expression increases after AMI²³¹, and its secretion by cardiomyocytes, mediated by the chemokine MCP-3, leads to hepatic prostaglandin E2 release. This dysregulates liver X receptor α (LXRα) and sterol regulatory element-binding protein 2 (SREBP-2) signalling, altering inflammatory and lipid metabolic gene expression and increasing hepatic triglycerides and VLDL levels²³².

Growth differentiation factor-15 (GDF15), a member of the transforming growth factor-β (TGF-β) superfamily, is another cardiokine with systemic effects. While not expressed in the healthy adult heart, GDF15 is secreted by cardiomyocytes under stress conditions such as ischemia/reperfusion and nitrosative stress²³³. Elevated GDF15 levels are associated with poor outcomes in HF^234–236. GDF15 is also secreted in other conditions, including exercise, obesity²³⁷, and aging^238–240, and acts centrally to suppress appetite and regulate energy balance^241,242. In pediatric heart disease, cardiomyocyte-derived GDF15 impairs growth hormone signalling in the liver, contributing to growth failure²⁴³. Recently, GDF15 was shown to improve insulin sensitivity in diet-induced obesity by enhancing β-adrenergic signalling in tissues including the liver²⁴⁴. Further research is needed to clarify its role in heart disease.

Finally, Mitsugumin 53 (MG53), an E3 ligase secreted by cardiomyocytes and myocytes in response to elevated glucose or insulin, modulates whole-body insulin sensitivity. MG53 inhibits insulin receptor signalling via extracellular blockade and intracellular ubiquitination, reducing Akt phosphorylation in the liver, skeletal muscle, heart, and visceral fat²⁴⁵.

While evidence supports the heart’s ability to signal to the liver via endocrine factors, only a few heart-secreted factors have been characterized to date. For many of these, their impact on liver physiology and mechanisms of action, particularly in cardiac disease, remain poorly understood. Further research is needed to fully elucidate these heart-liver interactions and their implications for systemic metabolism.

Circadian rhythm: a master regulator of liver-heart axis

Along with direct communication via hepatokines and cardiokines, liver and heart functions are coordinated within a time-dependent framework that influences the homeostasis of both organs under overarching regulation by the brain. This framework is composed of circadian rhythm functions – a cluster of pathways that connect the liver and heart in both physiological and pathophysiological states (Figure 1). Circadian rhythms – cycles which exist and repeat across a 24-hour period – optimize fundamental aspects of cellular physiology, such as proliferation, growth, and metabolism, and govern whole-body functions like sleep/wake cycles and feeding behaviour. At the core of these 24-hour rhythms is a cell-autonomous molecular oscillator present in every cell. The molecular clock consists of core clock components that generate 24-hours rhythms in the expression of clock genes (Bmal1/Arntl, Clock, Cry1/2, Per1/2, and Nr1d1/2) and clock-output genes via coupled transcriptional and translational feedback loops^246,247. Correct timing of these molecular clocks relies on entrainment factors called zeitgebers (time givers). For the central clock in the suprachiasmatic nucleus (SCN), light is the primary zeitgeber, while peripheral clocks in other tissues are entrained by neuronal, endocrine, and feeding-related signals^248–252. Disruptions to circadian rhythms—caused by chronic jet lag, shift work, or genetic alterations—are linked to a range of cardiometabolic disorders, including T2D, obesity, metabolic liver diseases, and HF^5–8. Conversely, strategies like time-restricted eating (TRE) and light therapy can strengthen circadian rhythms and improve cardiometabolic health^253,254.

As a central processor of whole-body metabolism, the liver is profoundly influenced by circadian rhythms⁷. Approximately 15% of the liver’s transcripts exhibit diurnal oscillations, with peaks timed to feeding and fasting cycles^255–257. These oscillations regulate critical metabolic processes, including glycogenesis, glycogenolysis, gluconeogenesis, lipogenesis, and FA oxidation, enabling the liver to anticipate and respond to nutrient availability. Glycogenesis and lipogenesis in the liver are driven by rhythmic activation of enzymes such as glycogen synthase (GYS1/2)^258,259 and of the lipogenic transcription factor SREBP1c^260,261. Core clock genes tightly regulate also catabolic pathways activated during fasting. For example, cryptochrome (CRY) proteins repress gluconeogenic enzymes²⁶² and period (PER) proteins regulate the circadian expression of mitochondrial enzymes to drive daily rhythms in mitochondrial respiration²⁶³. Hormonal signals like insulin and glucagon further synchronize hepatic rhythms with nutrient availability, ensuring a balance between energy storage and mobilization^264,265. Disruption of these rhythms—through irregular eating patterns or genetic mutations in clock genes—can lead to metabolic imbalances, increasing the risk of liver disease. For instance, liver-specific deletion of Bmal1 impairs glucose homeostasis, promoting IR and liver fat accumulation²⁶⁶. Additionally, the gut microbiome and its oscillatory species, and the metabolites they produce play a role in regulating hepatic metabolic homeostasis^267,268.

The heart, similar to the liver, operates under precise circadian regulation²⁶⁹. Unlike the liver, however, the heart relies primarily on oxidative metabolism, with its fuel preferences shifting between glucose and FAs across the day. During the active phase, the heart preferentially uses glucose, while FAs dominate during the rest phase. These shifts align with nutrient availability and metabolic activity in other tissues. The cell-autonomous clock of cardiomyocytes orchestrates these metabolic rhythms by regulating the expression of enzymes involved in glucose uptake, glycolysis, mitochondrial oxidative phosphorylation and lipid homeostasis. For example, BMAL1 enhances myocardial glucose oxidation during the active phase²⁷⁰, while REV-ERBs modulate fatty acid oxidation²⁷¹. Disruption of these rhythms – through shift work or sleep deprivation – impairs myocardial energy homeostasis, increases oxidative stress, and contributes to CVD. Studies in mice show that deleting core clock genes (Bmal1, Per1/2, Rev-erba/b) in the heart leads to impaired contractility, hypertrophic remodelling, HF, and increased susceptibility to IHD⁹. Circadian regulations extend beyond energetics. For example, hepatic enzymes for xenobiotic detoxification peak during rest, while those for glucose and lipid metabolism peak during activity^272,273.

Together, these findings underscore the intricate role of circadian rhythms in coordinating liver and heart function, extending beyond energy metabolism to include diverse physiological processes. Disruption of these rhythms can compromise organ-specific and systemic homeostasis, highlighting circadian alignment as a potential therapeutic target in liver-heart axis disorders.

6. Methods to Study Heart-Liver Interactions

Animal models are critical for elucidating complex interorgan interactions such as the liver-heart axis (Figure 3). Exploring cardiac involvement and ASCVD progression in liver-specific MASLD animal models can help in recognizing the role of liver pathology in CVD^274–276. Comparing cardiac disease in MASLD animal models with²⁷⁷ vs without^278,279 systemic metabolic alterations (e.g. obesity, IR) can help in dissecting liver-specific vs systemic causes of CVD. Diet-induced MASLD models are suited for investigating changes in hepatic secretory pathways²⁸⁰, leading to cardiac disease. Models of ALD can be used to track liver and heart damages of alcohol intake²⁸¹. Models of HF can similarly be leveraged to study heart-to-liver communication^189,282. Testing dietary inteerventions into genetically diverse mouse panels such as the Hybrid Mouse Diversity Panel (HMDP)²⁸³ allow cross-tissue transcriptomic analyses to map liver-derived and heart-derived signaling factors. Integrating findings from murine models with human patient-derived tissues enhances translational relevance²⁸². Together, these integrated approaches provide a powerful framework to mechanistically dissect and therapeutically target liver-heart communication in cardiometabolic disease.

Figure 3 – Research tools to explore cardiometabolic liver-heart crosstalk.

Schematic overview of experimental and analytical approaches used to investigate molecular, cellular, and systemic mechanisms underlying the interaction between liver and heart in cardiometabolic disease.

Navigating through the many animal models of liver and heart disease can be challenging. Table 1 provides a summary of key preclinical models, while a detailed descriptions for MASLD^284,285, ALD and cirrhosis²⁸⁶, HFrEF/IHD²⁸⁷, and HFpEF^288,289 animal models can be found in dedicated review articles.

Table 1 -. Preclinical Animal Models of Liver and Heart Disease.

Animal Model	Description	Pro	Cons	Refs
MASLD - Metabolic dysfunction-associated steatotic liver disease
DIAMOND model	Isogenic C57BL/6J × 129S1/SvImJ mice; HFD, high-carbohydrate diet + glucose-fructose in drinking water	Recapitulates full MASLD spectrum (steatosis, ballooning, inflammation, fibrosis); includes IR and dyslipidaemia	Long feeding time; strain-specific differences	277
AMLN diet model	HFHS diet inducing progressive steatosis and fibrosis	Strong MASLD features; systemic metabolic dysfunction	Slower fibrosis development; requires long dietary exposure	346
MC4R-KO + Western diet	Hyperphagic knockout mice developing obesity, severe steatohepatitis, fibrosis, HCC	Rapid MASLD progression; advanced fibrosis and metabolic dysfunction	Genetic manipulation may not fully mirror human variability	347
APOE*3-Leiden.CETP + Western diet	Humanized lipoprotein metabolism; steatosis, MASH, fibrosis, ASCVD	Combines liver and cardiovascular phenotypes; dyslipidaemia and IR present	Complex genetics; cost and breeding complexity	348
STAM model	Neonatal streptozotocin + HFD; diabetes, steatohepatitis, fibrosis, HCC without obesity	No obesity/dyslipidaemia confounding (useful to separate liver vs systemic effects); diabetes-specific MASLD model	Limited systemic metabolic features	278
MCD diet	Methionine- and choline-deficient diet causing steatohepatitis and fibrosis without obesity	Rapid fibrosis induction; no IR/obesity (useful to separate liver vs systemic effects)	Severe weight loss; poor metabolic relevance	279
ALD - Alcohol-associated liver disease
ADW model	Alcohol in drinking water; mild steatosis and inflammation	Simple and low-cost; voluntary intake	Limited BAC; mild liver injury	349,350
DID model	Binge-like alcohol intake; increased BAC; early liver damage	Models binge drinking; higher BAC	Limited to early ALD; lacks fibrosis	351,352
Lieber-DeCarli (LdC) diet	Liquid diet with incorporated ethanol; steatosis and inflammation	Controlled chronic exposure; reliable induction	Requires second-hit for fibrosis; limited advanced pathology	353,354
NIAAA model	LdC diet + acute ethanol binge; severe steatohepatitis	More severe liver damage; immune infiltration	Still lacks advanced fibrosis	281
Tsukamoto-French model	Intragastric ethanol infusion; high BAC; progressive liver injury	Best replication of human ALD features; necrosis, fibrosis, inflammation	Technically complex; high resource needs	355,356
Cirrhosis
CCl4	Chronic hepatotoxin exposure (intraperitoneal or inhalation); toxic liver injury and fibrosis	Well-established; portal hypertension achievable	Strain-dependent; fibrosis partially reversible	357–359
TAA	Chronic hepatotoxin exposure; stable periportal/lobular fibrosis	Highly reproducible; independent of genetic background	Longer exposure needed; limited spontaneous decompensation	360–362
cBDL	Surgical bile duct ligation; cholestatic fibrosis	Rapid cirrhosis induction; cholestatic injury model	Surgical expertise required; bile excretion impairment	363,364
Heart failure with reduced ejection fraction (HFrEF) – Ischemic heart disease (IHD)
TAC	Transverse aortic constriction; pressure overload → HFrEF	Reproducible; mechanistic relevance; concentric hypertrophy	Technically demanding; mortality risk	365–368
LAD ligation (AMI model)	Coronary artery ligation inducing myocardial infarction	Gold standard ischemic HFrEF model	Irreversible infarction; requires precise surgery	369
Doxorubicin-induced	Chemotherapy-induced cardiomyopathy with fibrosis and low LVEF	Non-surgical; mimics clinical cardiotoxicity	Strain-sensitive; limited translation	370,371
Isoproterenol-induced	β-adrenergic overstimulation causing cardiac fibrosis and dysfunction	Non-invasive; rapid model	Limited chronicity; non-ischemic	372–374
Angiotensin II-induced	Chronic hypertension model with HFrEF features	Relevant RAAS activation; non-surgical	Hypertension may dominate phenotype; strain-dependent	375
Heart failure with preserved ejection fraction (HFpEF)
HFD + L-NAME	HFD + nitric oxide synthase inhibition; obesity, hypertension, IR, diastolic dysfunction	Recapitulates cardiometabolic HFpEF	NO pathway-specific; supra-physiological stress	148
ZSF1 obese rat	Genetic hypertension, hyperlipidaemia, IR, renal impairment, diastolic dysfunction	Robust cardiometabolic syndrome; systemic disease	Mild hepatic involvement; costly	376
Aged C57BL/6J + HFD + angiotensin II	Aging plus metabolic + hypertensive stress; HFpEF-like features	Relevant aging/metabolic HFpEF	Hepatic phenotype poorly characterized	377
DOCA-salt model	Mineralocorticoid excess; hypertension and diastolic dysfunction	Non-metabolic HFpEF; pure pressure overload	No obesity; no IR	378
Renin + HFD model	Adenoviral-mediated renin overexpression + HFD; RAAS-driven HFpEF	Strong RAAS activation; cardiometabolic HFpEF	Supra-physiological model; complex	379

Summary of commonly used animal models for MASLD, ALD, cirrhosis, HFrEF/IHD, and HFpEF, with their main advantages and limitations. ALD, Alcohol-associated liver disease; AMI, Acute myocardial infarction; ASCVD, Atherosclerotic cardiovascular disease; BAC, Blood alcohol concentration; CCl₄, Carbon tetrachloride; cBDL, Common bile duct ligation; DIAMOND, Diet-induced animal model of non-alcoholic fatty liver disease; DOCA, Deoxycorticosterone acetate; HFD, High-fat diet; HFHS, High-fat, high-sucrose diet; HFpEF, Heart failure with preserved ejection fraction; HFrEF, Heart failure with reduced ejection fraction; IHD, Ischemic heart disease; IR, Insulin resistance; LdC, Lieber-DeCarli; LAD, Left anterior descending coronary artery; MASLD, Metabolic dysfunction-associated steatotic liver disease; NOS, Nitric oxide synthase; RAAS, Renin–angiotensin–aldosterone system; TAC, Transverse aortic constriction; TAA, Thioacetamide.

Systems Biology Approaches: Integration of omics to map heart-liver communication

Systems biology approaches are novel research tools for uncovering complex inter-organ signalling pathways by integrating large-scale multi-omics datasets (Figure 3). One of the most powerful techniques in this area is the Quantitative Endocrine Network Interaction Estimation (QENIE) method^290,291. The core premise of QENIE is that if a signalling relationship exists, the expression of a gene encoding a secreted protein in the origin tissue will correlate with expression changes in genes of the target tissue. QENIE leverages gene expression data from genetically diverse populations, such as the HMDP, or human cohorts (i.e. GTEx), to identify secreted proteins in the origin tissue (e.g., liver) that correlate with gene expression patterns in target (e.g., heart). Biweight midcorrelation (bicor)²⁹² is used to assess cross-tissue associations, and the calculated Ssec score ranks secreted proteins based on the strength of their correlations with genes in target tissues. Integration with secretome databases (e.g., UniProt) and tissue-specific expression profiles further refines candidate prioritization.

A QENIE framework has been successfully used to identify three liver-derived secreted proteins, namely HGFAC, C8G, and FXI, with potential roles in liver-heart crosstalk¹⁸⁹. Through cross-tissue transcriptomic correlation in the HMDP, FXI emerged as one of the most interesting targets in liver-heart crosstalk¹⁸⁹ and was validated as a cardioprotective factor, able to improve diastolic function and attenuate cardiac inflammation and fibrosis. FXI’s proteolytic activity was shown to be essential for cleaving and activating BMP7, leading to the suppression of inflammation- and fibrosis-related gene expression¹⁸⁹. HGFAC (hepatocyte growth factor activator) was identified as an additional crosstalk candidate¹⁸⁹ and its specific role in driving HFpEF phenotype is under investigation. The third candidate, C8G (complement component C8 gamma chain), was shown to reduce heart weight in the HFpEF model¹⁸⁹. Recently, applying a multi-tissue transcriptomic approach in a mouse model of HFpEF, among 86 liver-secreted candidates, serum amyloid A proteins (SAA1 and SAA4) emerged as HFpEF- specific mediators of liver-heart crosstalk²⁸². Circulating levels of these proteins were increased in HFpEF mouse models and in human HFpEF and MASLD cohorts. Notably, their expression was correlated with cardiac fibrosis and ECM remodelling pathways. Taken together, these studies underscore the critical role of liver-to-heart signalling in driving key features of HFpEF and showcase the power of integrated -omics and systems genetics to reveal novel mediators of liver-heart communication and beyond.

Mediators of interorgan crosstalk can be also investigated using web-based informatic hypothesis-generating interfaces, such as the HMDP systems genetics webpage (https://systems.genetics.ucla.edu/HMDP/) or the Gene-derived correlation across tissues (GD-CAT) webpage (https://pipeline.biochem.uci.edu/gtex/). The former allows to identify statistical associations between genes, SNPs, and/or clinical traits of interest through a range of datasets, such as, mice fed a standard chow-diet, a HFHS diet, and mice exposed to isoproterenol to induce HFrEF. This tool allows to search and generate Manhattan plots, look up quantitative trait loci (QTL), identify gene, SNP, and trait correlations, and visualize genome-wide hotspots; all in a manner that allows the user to generate new and interesting investigatory directions. Utilizing much of the same data in a uniquely distinct manner, the latter (GD-CAT), offers a more focused view of cross-tissue communication built from QENIE methods. GD-CAT allows one to peer into HMDP data (chow diet or HFHS diet fed mice) and GTEx (male, female, or combined) data to investigate cross-tissue gene expression associations. By serving as an easy to use, efficient, in silico hypothesis generating and/or solidifying system, GD-CAT is an extremely valuable tool to explore novel secreted factors mediating liver-heart interactions.

Approaches like QENIE, cross-tissue transcriptomic correlation, and proteomic validation enable a comprehensive understanding of the endocrine networks involved in cardiometabolic disease. Web-based informatic interfaces like the HMDP Shiney app and GD-CAT make novel or previously underappreciated cross-tissue connections easy-to-use and thus accessible to the whole scientific community.

Secretome Profiling: Advances in proximity labeling techniques to track inter-organ signaling molecules.

Proximity labelling has emerged as a cutting-edge technique for tagging proteins synthesized in specific subcellular compartments within living organisms (Figure 3). This method relies on engineered biotin ligase enzymes that, in the presence of a substrate, covalently tag endogenous proteins within a radius of a few nanometers. The biotinylated proteins can then be isolated using streptavidin-based enrichment and identified via mass spectrometry²⁹³. Recent advancements in biotin ligase engineering, enabling faster and more efficient labelling in vivo, have expanded the application of this technique to in vivo secretome studies²⁹⁴. Proximity labelling is particularly valuable for studying interorgan communication in both physiological and pathological conditions for several reasons. First, the biotin ligase enzyme can be expressed in a cell-type-specific manner using adenoviral-associated vectors (AAVs) driven by tissue-specific promoters^295,296 or through transgenic animal models crossed with Cre recombinase lines^297,298. This allows researchers to precisely determine the cellular and tissue origins of secreted proteins in the animal model of interest (i.e. mouse models of MASLD and/or HFpEF) Second, the biotinylation event is initiated only upon substrate delivery, providing temporal control over the labelling process. This flexibility enables researchers to tailor the labelling period to the specific context, whether it involves acute events (hours) or chronic conditions (days).

To date, cell-type-specific proximity labelling has been successfully used to profile the liver secretome under various physiological and disease conditions. For example, using the TurboID system, a recent study identified carboxylesterase enzymes CES2A and CES2C as the most exercise-responsive proteins secreted by the liver. Further characterization revealed their anti-obesogenic and anti-diabetic properties, uncovering new mechanisms of tissue-tissue communication underlying the benefits of physical activity²⁹⁹. Another study demonstrated that hepatic secretion of the glycoprotein Fetuin-A is altered in IR conditions²⁹⁶. While elevated circulating Fetuin-A levels are associated with MASLD and IR³⁰⁰, they are reduced in HF patients with liver hypoperfusion, suggesting impaired hepatic secretion in these patients³⁰¹. Importantly, proximity labelling can also capture proteins secreted via non-conventional pathways, which may play a critical role in certain conditions. For instance, targeting the biotin ligase to the endoplasmic reticulum (ER) allows for the identification of proteins secreted through the conventional ER-to-Golgi pathway, while targeting the cytoplasmic compartment enables the detection of proteins undergoing unconventional export. Using this dual approach, is was observed that a HFHS diet suppress conventional protein secretion while strongly inducing the unconventional secretion of the enzyme betaine-homocysteine methyltransferase (BHMT)²⁹⁵. This highlights the importance of studying unconventional secretion pathways in metabolic diseases.

Given its versatility, proximity labelling is a powerful tool for investigating cell-specific secretomes and inter-organ communication mechanisms in cardiometabolic diseases, including HFpEF. By providing spatial, temporal, and cell-type-specific resolution, this approach holds great promise for uncovering novel biomarkers and therapeutic targets in complex diseases.

Modelling inter-organ crosstalk: Organoids, Organ-on-Chip, and Precision-cut-tissue slices

To understand disease mechanisms and develop effective treatments, researchers require models that accurately mimic the complexities of human biology. Traditional in vitro models like 2D cell cultures lack the structural and functional complexity of human tissues, while animal models, though valuable, are expensive, time-consuming, and may not fully replicate human biology due to genetic and physiological differences ^302,303. The use of patient-derived material represents a highly relevant and versatile model for bridging the gap between pre-clinical models and translational research. Such material can be used for systems such as organoids, organ-on-chip and precision-cut tissue slices. Importantly, these systems can be used for the generation of -omic datasets (transcriptomics, proteomics, metabolomics), correlation of data with clinical features, and can serve as a platform for secretome studies.

Organoids

Recent advancements in organoid and organ-on-chip systems have transformed in vitro modelling by providing physiologically relevant platforms for studying organ development, disease mechanisms, and therapeutic responses (Figure 3). Organoids are three-dimensional, self-organizing structures derived from human cells^304,305 that closely mimic the architecture and functionality of native tissues. Organ-on-chip systems integrate microfluidic technologies that replicate organ-level functions by using hollow channels lined with living cells under controlled fluid flow. These systems can be interconnected to create multi-organ platforms, enabling the study of complex physiological processes and systemic interactions³⁰⁶. Together these models bridge the gap between traditional in vitro and in vivo models, enabling the investigation of cell-cell and inter-organ interactions, such as those between the heart and liver. This represents a significant leap forward in our ability to study complex biological systems and address human diseases with unprecedented precision.

Hepatic organoids, derived from sources such as primary liver tissue, embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs), have emerged as valuable in vitro models for hepatology research³⁰⁷. They recapitulate key hepatic functions such as metabolism, detoxification, and bile acid synthesis, making them extremely valuable for studying liver disorders and metabolic diseases. For instance, an ALD model co-culturing hepatocyte organoid with mesenchymal cells has been shown to replicate key phenotypes associated with ALD, such as oxidative stress, steatosis, and fibrosis upon alcohol exposure³⁰⁸. Similarly, multicellular organoids with hepatocytes, stellate, and Kupffer-like cells were shown to recapitulate features of MASLD, including steatosis and inflammation^309,310. Additionally, organoids derived from patients with MASH have been shown to preserve MASH phenotypes, including decrease in albumin production, steatosis, and sensitivity to apoptosis³¹¹, providing powerful tools for investigating liver pathophysiology, disease progression, and testing therapeutic candidates.

Cardiac organoids, particularly engineered human myocardium (EHM) derived from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), have emerged as a valuable tool for modelling cardiac diseases such as HF. These systems replicate pathological features like contractile dysfunction, hypertrophy, and cell death under chronic stress conditions, such as catecholamine exposure³¹². Advances in cardiac organoid development are extending their utility to broader cardiovascular research, including arrhythmias and myocardial infarction.

Organ-on-chip

Organ-on-chip technology bridges the gap between static in vitro models and dynamic physiological conditions by incorporating microfluidic systems to simulate blood flow and nutrient exchange³¹³. These systems enable co-culture of liver and heart organoids to study systemic diseases. For example, a liver-on-chip system analyzing increased hydrodynamic pressure in liver sinusoidal endothelial cells identified novel biomarkers for portal hypertension³¹⁴. Emerging multi-lineage organoid systems and microfluidic devices are advancing the study of heart-liver interactions. These models mimic inter-organ signalling, crucial for understanding diseases such as cardiac amyloidosis, where liver-derived proteins like transthyretin influence cardiac function³¹⁵. While these platforms offer dynamic insights into systemic diseases and novel therapeutic strategies, they are not without limitations³¹⁶. A significant challenge is the lack of a universal medium, such as blood, that can supply cells with essential nutrients and growth factors across diverse organ systems.

Precision-cut tissue slices

Precision-cut tissue slices retain the complex multicellular architecture, tissue-specific extracellular matrix, and physiological functions of the organ, and can be cultured ex vivo for several days^317,318. This makes them an excellent platform for studying intercellular communication and secreted factors, such as proteins, metabolites, and extracellular vesicles (EVs) (Figure 3).

The use of tissue slices has long been used in metabolic preclinical research. Today, advancements such as vibrating microtomes have refined the technique, enabling its application across a wide range of studies. For example, liver slices have proven as a valuable tool for investigating xenobiotic metabolism, testing anti-fibrotic drugs, and conducting toxicological studies. Importantly, slices obtained from patient biopsies allow researchers to study disease-specific pathological processes and evaluate the efficacy of pharmacological therapies^317,319. Similarly, myocardial slices preserve cardiac structure and function, making them ideal for studying cardiac metabolism, electrophysiology, contractility, and pharmacological safety^318,320. Slices from human failing hearts have been used to explore mechanisms of myocardial fibrosis in response to mechanical stress and to test potential anti-fibrotic treatments³²¹.

By closely mimicking in vivo conditions, precision-cut tissue slices provide a robust and human-relevant system for secretome analysis. Both the tissue and the culture medium can be analysed, enabling comprehensive profiling of secreted factors from clinically relevant tissues. For instance, the protein arylsulfatase A (ARSA) was identified as a MASLD/MASH induced hepatokine regulating systemic lysophospholipid metabolism and glycemia. Its increased secretion was first detected in the media of primary hepatocytes from a murine MASH model and later confirmed using precision-cut liver slices from healthy controls and patients with MASLD and MASH, highlighting the relevance in human disease³²². Similarly, liver-secreted hexosaminidase A (HEXA) was identified as a hepatokine mediating liver-to-skeletal muscle communication in MASLD. Elevated HEXA secretion was observed in the media of precision-cut liver slices from patients with MASLD compared to controls³²³. Another study demonstrated that liver-derived EVs regulate whole-body glucose homeostasis through inter-organ signalling to skeletal muscle and the pancreas. EV secretion was enhanced in early-stage MASH, and EVs isolated from the media of precision-cut liver slices from bariatric surgery patients improved glycaemic control in recipient mice, underscoring the translational potential of liver-secreted EVs³²⁴.

Overall, precision-cut tissue slices offer a powerful and physiologically relevant system for secretome analysis, with significant potential for discoveries that can be directly translated to clinical applications. However, a key limitation of the technique is the limited availability of viable tissue biopsies, particularly for heart tissue, which restricts the use of myocardial slices for studying cardiac-driven secretory events in heart disease.

Organoids, organ-on-chip, and precision-cut tissue systems are transformative tools for studying heart-liver interactions. As these technologies continue to evolve, they hold immense potential for the identification of the underlying mechanisms of MASLD, HFpEF and cardiometabolic disease, but also the identification of new potential targets for therapeutic intervention, paving the way for more personalized medicine and translational research.

6. Targeting metabolism to improve heart and liver function: mechanistic evidence

Exploring potential interactions between liver and heart, especially in the context of cardiometabolic diseases, should always aim not only at dissecting the complex underline pathophysiology: the ultimate goal is to find effective therapeutic strategies to break this axis. Several pharmacological and non-pharmacological interventions exist, targeting liver, heart or metabolic dysfunction on a systemic scale. For most, the effects on interorgan crosstalk are unknown but worth being explored.

Non-pharmacologic strategies form the foundation for managing metabolic dysfunction impacting both liver and heart health. Behavioral and environmental factors drive cardiometabolic disease by inducing oxidative stress, low-grade inflammation, IR, and lipid imbalance. TRE aligns food intake with circadian rhythms, improving glucose metabolism, reducing inflammation, and promoting weight loss^256,325,326. TRE has been shown to enhance insulin sensitivity and reduce cardiovascular risk markers^327–329. Whole-food-based diets like Mediterranean and DASH reduce hypertension, improve lipid profiles, and support liver function^330,331. Dietary fibre further improves glycaemic control and fosters gut microbial diversity³³².

Exercise, another pillar of metabolic non-pharmacological interventions, enhances mitochondrial efficiency, reduces inflammation, and supports both hepatic and cardiac health³³³. Aerobic training boosts cardiovascular function, while resistance training improves glucose uptake and insulin sensitivity³³⁴. Stress reduction, sleep hygiene, and avoiding toxins like alcohol and tobacco further enhance metabolic balance^335–337.

Altogether, dietary interventions and physical activity are the most effective, sustainable and safe interventions to be put in place to fight both liver and heart metabolic disease and thus reduce CVE. Despite strong evidence, barriers such as socio-economic status, time constraints, and knowledge gaps limit widespread adoption. Personalized interventions, community-based programs, and digital tools may help bridge this gap³³⁸.

Pharmacologic therapies provide essential support in patients with established liver or cardiac disease. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), such as empagliflozin and dapagliflozin, offer dual protection. They improve cardiovascular outcomes in patients with HF (either HFrEF or HFpEF) and ASCVD (including AMI), even in the absence of T2D³³⁹. Similarly, SGLT2i reduced hepatic steatosis and fibrosis in MASLD, although liver-specific endpoints in non-diabetic populations remain unclear^340,341. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide, and dual or triple incretin analogues (e.g., tirzepatide, retatrutide), reduce body weight, enhance insulin sensitivity, improve exercise performance and lower risk of cardiovascular death or worsening of HF in HFpEF patients^342,343. Semaglutide has shown steatohepatitis resolution without fibrosis improvement³⁴⁴, and ongoing trials will clarify broader hepatic benefits.

Overall, SGLT2i and GLP-1 RAs represent promising pharmacologic options for the simultaneous treatment of liver-heart metabolic disease. However, robust evidence from studies specifically designed to target multi-organ pathology—both in preclinical models and clinical settings—remains limited.

To fully understand the interorgan benefits and potential adverse interactions, metabolic interventions (potentially impacting on both liver and heart, such as non-pharmacological strategies, SGLT2i and GLP-1 RAs) must be rigorously tested in animal models, in vitro, and ex vivo platforms, simultaneously assessing liver and heart effects. Such interventions should be compared with organ-specific therapies (e.g. resmetirom, a thyroid hormone receptor-β agonist that improves steatohepatitis and fibrosis in patients with MASLD³⁴⁵) to test for secondary cardiac benefits. Similarly, the effects of cardiac-specific drugs should be observed in the liver. Mechanistic studies should aim at dissecting molecular pathways—such as inflammation, oxidative stress, mitochondrial dysfunction, and fibrosis—involved organ-specific vs interorgan effects.

Importantly, considering the large body of evidence indicating CVE as the primary cause of mortality and morbidity in MASLD (and possibly ALD and MetALD), clinical trials designed with CVE as primary endpoints (instead of liver-related events) are needed in MASLD/ALD/MetALD patients.

7. Challenges and Limitations in Advancing Liver-Heart Crosstalk Research

Advancing research on liver-heart crosstalk in cardiometabolic diseases presents several challenges that must be carefully addressed to ensure robust and translatable findings. At the core lies the complexity of the interorgan network itself – metabolic, hormonal, inflammatory, and circadian signals interact in a bidirectional and dynamic fashion, often producing pleiotropic effects that vary depending on disease stage, comorbidities, and context. For instance, hepatokines such as FGF21 or FXI may exert cardioprotective or pathogenic effects depending on the setting, complicating both mechanistic interpretation and therapeutic targeting.

Preclinical models, while essential, often fall short of replicating human disease in its full complexity. Most studies focus either on liver or heart pathology in isolation, and few models accurately capture the co-evolution of hepatic and cardiac dysfunction seen in conditions like MASLD-related HFpEF. Even in models that integrate multiple metabolic features, cardiac assessment in liver disease models – or hepatic profiling in heart failure models – is often incomplete or overlooked. Moreover, existing models typically reflect early or exaggerated disease states that may not mirror the gradual progression observed in humans.

Similarly, human translation is halted by limitations in biomarker validation and standardization. While multi-omics approaches and computational frameworks have identified promising candidates mediating liver-heart signaling, robust validation in large, diverse patient cohorts is often lacking. Circulating levels of hepatokines or cardiokines may not reflect tissue-level activity, and interindividual variation – including genetics, diet, microbiome, and circadian rhythms – adds further complexity to interpretation.

The temporal dynamics of liver-heart communication are also understudied. Most available data derive from cross-sectional analyses, failing to capture how interorgan signaling evolves over time or in response to acute stressors. This makes more difficult to provide causal inference and the development of time-sensitive therapeutic interventions. Furthermore, emerging technologies such as proximity labeling, organ-on-chip, and spatial transcriptomics hold great promise but remain limited by technical complexity, cost, and accessibility. Broad adoption and cross-validation across platforms are needed.

Lastly, therapeutic translation is challenged by potential bidirectional effects. Interventions targeting one organ may have unintended consequences on the other, particularly given the liver’s central role in drug metabolism. As such, a more integrated, systems-level approach is essential to move beyond single-organ paradigms and unlock the full clinical potential of targeting the liver-heart axis.

9. Conclusion

Understanding liver–heart crosstalk marks a pivotal shift in how we conceptualize CVDs—not as isolated organ dysfunctions but as an integrated, systemic syndrome. Recognizing the liver as a driver and amplifier of CVDs demands that we reframe basic research, datasets analysis, diagnostic strategies and therapeutic interventions to consider metabolic liver disease as a modifiable cardiovascular risk factor. This shift has profound implications for early screening, risk stratification, and patient management across disciplines.

The development and application of mechanistically relevant animal models and advanced in vitro and ex vivo platforms that recapitulate liver–heart interactions is critical. These systems are essential for probing interorgan signalling networks, uncovering novel molecular targets, and validating cross-organ effects of emerging therapies. Without such translational models, the causal links between hepatic pathology and cardiovascular disease remain speculative and therapeutic translation remains limited.

Interventions that target shared pathophysiological mechanisms—such as inflammation, fibrosis, lipotoxicity, and insulin resistance—hold promise for disrupting the feed-forward loops linking hepatic and cardiac dysfunction. However, most current pharmacologic trials focus on single-organ endpoints. To effectively deviate the natural history of multisystemic cardiometabolic disease, clinical trials must be intentionally designed with multi-organ outcomes in mind, including endpoints that reflect improvements in both hepatic and cardiac health.

The field stands at an inflection point: integrated approaches to research and clinical care are urgently needed to prevent and treat the growing burden of cardiometabolic disease. Collaborative efforts between hepatologists, cardiologists, internists, endocrinologists, and translational scientists will be key to unlocking therapies that reflect the biological reality of these interdependent organs. Going forward, precision medicine for cardiometabolic disease must be organ-aware, mechanism-driven, and systemically informed.

Nonstandard Abbreviations List

AMLN

Amylin liver disease model

ARIC

Atherosclerosis Risk in Communities Study

ASCVD

Atherosclerotic Cardiovascular Disease

ATTR

Transthyretin amyloidosis

BCAA

Branched-chain amino acids

BDH1

β-hydroxybutyrate dehydrogenase 1

BHMT

Betaine-homocysteine methyltransferase

BMAL1

Brain and Muscle ARNT-Like 1

DASH

Dietary Approaches to Stop Hypertension

DIAMOND

Diet-Induced Animal Model of NAFLD

DOCA

Deoxycorticosterone acetate

HEXA

Hexosaminidase A

HFHS

High-Fat, High-Sucrose diet

HGFAC

Hepatocyte Growth Factor Activator

HMDP

Hybrid Mouse Diversity Panel

HMGB1

High-Mobility Group Box 1

MASH

Metabolic dysfunction-associated steatohepatitis

MASLD

Metabolic dysfunction-associated steatotic liver disease

PCSK6

Proprotein Convertase Subtilisin/Kexin Type 6

QENIE

Quantitative Endocrine Network Interaction Estimation

STAM

Streptozotocin–High-Fat Diet Model

STAT3

Signal Transducer and Activator of Transcription 3

VLDL

Very-Low-Density Lipoprotein

WGCNA

Weighted Gene Co-expression Network Analysis

ZSF1

Zucker Spontaneously Hypertensive Fatty rat model