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.