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

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.

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.