Extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From intercellular signaling to clinical translation

Table 1 Extracellular vesicle cargo and functional effects in metabolic dysfunction-associated steatotic liver disease progression

Donor cells/ EV sources	Recipient cells	EV cargoes	EV effects	Ref.
Hepatocyte-derived EVs to other cells
Lipotoxic hepatocytes, primary mouse hepatocytes and Huh7 cells treated with PA or LPC	Macrophages, BMDMs	CXCL10	Recruits macrophages and exacerbates inflammation	[65,67]
Lipotoxic hepatocytes, mouse hepatocyte cell lines, primary mouse hepatocytes, and Huh7 cells treated with PA or OA	Macrophages, BMDMs	Ceramide, S1P	Activates IRE1α, recruits macrophages, and amplifies liver inflammation	[36,68]
Lipotoxic hepatocytes, primary mouse hepatocytes and Huh7 cells treated with LPC	Macrophages, BMDMs	TRAIL	Activates macrophages via RIP1-DR5 pathway, worsening inflammation	[64]
Primary mouse hepatocytes	Macrophages, RAW264.7 cells	mtDNA	Activates macrophages, increasing inflammatory signaling	[24]
Lipotoxic hepatocytes, LO2 cells treated with PA, Huh7 cells treated with ox-LDL and MβCD cholesterol	Macrophages, THP-1 cell diferentiation	miR-122-5p, miR-192-5p, miR-9-5p	Polarizes macrophages to M1, enhances inflammatory responses	[70,71,72]
Hypoxia in fat-laden liver cells, primary mouse hepatocytes and HepG2 treated with PA + OA	HFD-mouse Kupffer cells	mtDNA	Activates TLR9, inducing TNFα and IL-1β secretion	[73]
Primary rat hepatocytes	Primary rat Kupffer cells	N/A	Stimulates inflammation in Kupffer cells	[74]
Lipotoxic hepatocytes, LO2 cells treated with PA	Primary human Kupffer cells	RBP4	Promotes M1 polarization, increases ROS and TNF-α production	[75]
Lipotoxic hepatocytes, HepG2 treated with PA + OA, chemical hypoxia induction hepatocytes, treated with CoCl2	HSCs, LX-2 cells	Hypoxia-induced cargo	Promotes pro-fibrotic gene expression and fibrosis	[66,76]
Lipotoxic hepatocytes, primary mouse hepatocytes and HepG2 cells treated with PA	HSCs, LX-2 cells, primary mouse HSCs	miR-128-3p	Suppresses PPAR-γ, enhances pro-fibrogenic gene expression, proliferation, and chemotactic responses	[66]
Lipotoxic hepatocytes, primary hepatocytes, LO2 cells treated with PA	HSCs, LX-2 cells	miR-1297	Targets PTEN, leading to HSC activation and proliferation via PI3K/AKT signaling	[77]
Lipotoxic hepatocytes, primary hepatocytes treated with PA	HSCs, LX-2 cells	miR-107	Activates Wnt signaling, promoting HSC activation	[78]
Lipotoxic hepatocytes, primary rat hepatocytes treated with PA + OA	HSCs, primary rat HSCs	Various mRNAs and miRNAs	Induces pro-fibrotic and pro-senescent phenotype, reduce fibrosis, increase ROS and senescence markers, mediated via AKT-mTOR pathway	[79]
Lipotoxic hepatocytes, primary rat hepatocytes, HepG2 cells treated with PA	Endothelial cells, primary rat endothelial cells, HUVECs	VNN1	Promotes angiogenesis and endothelial migration	[61]
Lipotoxic hepatocytes, primary mouse hepatocytes, Huh7 cells treated with PA	Endothelial cells, primary rat endothelial cells, HUVECs	miR-1	Promotes endothelial inflammation and atherogenesis	[80]
Lipotoxic hepatocytes, primary mouse hepatocytes, Huh7 cells treated with LPC	Endothelial cells, primary mouse LSECs	ITGβ1	Induces monocyte adhesion to LSECs, facilitating inflammation and fibrosis	[81]
Primary mouse hepatocytes	Adipocytes, 3T3-L1 cell differentiation	let-7e-5p	Promotes adipogenesis and lipid accumulation	[82]
Immune cell-derived EVs to other cells
Neutrophills isolated from CCL4- and MCD-treated mice	Macrophages, mouse primary hepatic macrophages	miR-223	Promotes restorative macrophage phenotype, reduces HSC activation and fibrosis	[84]
Neutrophills isolated from HFD-treated mice	Lipotoxic hepatocytes, AML12 cells treated with PA	miR-223	Inhibits hepatic inflammatory and fibrogenic gene expression in LDLR/ApoE dependent manner	[55]
Macrophages and neutrophils isolated from IL-6 knockout HFD-treated mice	Hepatocytes, primary mouse hepatocytes	miR-223	Suppresses fibrotic gene and immflmatory gene expression, reducing liver fibrosis	[87]
Macrophages, human PBMC dirferentiation	Lipotoxic hepatocytes, Huh7 treated with PA	miR-223	Reduces inflammatory and fibrotic responses within the liver by suppressing FOXO3 and TAZ through LDLR/ApoE axis	[56]
Macrophages, RAW264.7 cells	HSCs, primary mouse HSCs isolated from CCL4-induced mice	miR-500	Activates TGF-β/Smad pathway, accelerating fibrosis	[88]
Kupffer cells isolated from MASH mice	Hepatocytes, HSCs isolated from MASH mice	miR-690	Regulates inflammation, fibrogenesis, and lipogenesis	[89]
Other cell-derived EVs
Visceral adipose tissue isolated from obese and lean patients	HSCs	N/A	Alters liver matrix regulation by increasing TIMP, Smad-3, integrin, and MMP-9 expression in HSCs	[90]
HSCs, primary human HSCs, LX-2 cells	HSCs, primary human HSCs, LX-2 cells	PDGFRα, SHP2	Promotes HSC migration and fibrosis progression by suppressing REDD1 and enhancing mTOR	[91,92]
BMSCs	HSCs	miR-192-5p	Inhibits HSC activation by targeting PPP2R3A	[93]
ADMSCs isolated from CCl4-induced mice	HSCs	miR-150-5p	Suppresses CXCL1, reducing fibrosis	[94]
MSCs isolated from the human umbilical cords	HSCs, LX-2 cells	miR-4465	Reduces fibrosis by altering LOXL2 expression	[95]
Gut-derived EVs, HFD-fed mice	Hepatocytes, HSCs, HFD-fed mice, Mki67 mice	HMGB1	Activates cGAS/STING pathway, driving inflammation and fibrosis	[96,97]

EV: Extracellular vesicle; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; PA: Palmitic acid; LPC: Lysophosphatidylcholine; BMDMs: Bone marrow-derived macrophages; CXCL: C-X-C motif chemokine ligand; OA: Oleic acid; S1P: Sphingosine-1-phosphate; IRE1α: Inositol-requiring enzyme 1 alpha; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand; RIP1-DR5: Receptor-interacting serine/threonine-protein kinase 1-death receptor 5; mtDNA: Mitochondrial DNA; ox-LDL: Oxidized low-density lipoprotein; MβCD: Methyl-β-cyclodextrin; HFD: High-fat diet; TLR9: Toll-like receptor 9; TNFα: Tumor necrosis factor alpha; IL-1β: Interleukin-1 beta; LO2: Human normal liver cell line LO2; RBP4: Retinol-binding protein 4; ROS: Reactive oxygen species; HSCs: Hepatic stellate cells; PPAR-γ: Peroxisome proliferator-activated receptor gamma; PTEN: Phosphatase and tensin homolog; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; AKT-mTOR: Protein kinase B-mammalian target of rapamycin; VNN1: Vanin 1; HUVECs: Human umbilical vein endothelial cells; ITGβ1: Integrin subunit beta 1; LSECs: Liver sinusoidal endothelial cells; CCL4: Carbon tetrachloride; MCD: Methionine-choline deficient; LDLR: Low-density lipoprotein receptor; ApoE: Apolipoprotein E; TGF-β: Transforming growth factor beta; Smad: Small mothers against decapentaplegic; TIMP: Tissue inhibitor of metalloproteinases; MMP-9: Matrix metalloproteinase 9; PDGFRα: Platelet-derived growth factor receptor alpha; SHP2: Src homology region 2 domain-containing phosphatase-2; REDD1: Regulated in development and DNA damage responses 1; mTOR: Mammalian target of rapamycin; BMSCs: Bone marrow mesenchymal stem cells; PPP2R3A: Protein phosphatase 2 regulatory subunit B alpha; ADMSCs: Adipose-derived mesenchymal stem cells; CXCL1: C-X-C motif chemokine ligand 1; MSCs: Mesenchymal stem cells; HMGB1: High mobility group box 1; cGAS/STING: Cyclic guanosine monophosphate–adenosine monophosphate synthase/stimulator of interferon genes; N/A: Not applicable; FOXO3: Forkhead box O3; TAZ: Transcriptional coactivator with PDZ-binding motif.