Roles of hepatic immunity in metabolic dysfunction-associated steatotic liver disease: Cellular and molecular mechanisms and clinical trials

Table 1 Roles of different innate immune cells in the progression of metabolic dysfunction-associated steatotic liver disease

Cells	Markers	Functions	Ref.
cDCs	CD103	Adoptive transfer of CD103-expressing cDCs protected liver inflammation and damage in Batf3-deficient animals with a high sucrose diet or MCD diet during MASH progression	Heier et al[15]
cDCs	XCR1+	XCR1+ cDC1 cells influence inflammatory T cell reprogramming and exacerbate MASH development	Deczkowska et al[16]
Macrophages	MERTK	Ablation of MERTK signaling by disintegrin and metalloproteinase domain-containing protein 17 decreased MASH progression	Cai et al[23]
Macrophages	Ly6C+OPN+	Infiltration of Ly6C+OPN+ lipid-associated macrophages promoted MASH progression	Kui et al[38]
Neutrophils	Ly6G+H3Cit+	Infiltration of Ly6G+H3Cit+ neutrophils promoted MASH progression	Kui et al[38]
NK cells	CXCR3+	CXCR3+ NK cells decreased liver inflammation in MCD-induced MASH in mice	Fan et al[44]
NKT cells	IL-17A+	IL-17A-expressing invariant NKT cells in peripheral blood mononuclear cells were associated with MASH progression in patients	Maricic et al[51]
MAIT cells	TCRVa7.2+ CD161high CD3+	The frequency of MAIT cells in circulating blood in patients with MASH decreased compared to that in the group with steatosis or healthy controls	Waller et al[52]
ILCs	CD45+ TCRβ- B220-; NK1.1+ CD49a+ CD49b-	Increasing the frequency of ILC1 frequency by fecal microbiota transplantation and indole-3-carbinol inhibited MASLD	Hou et al[58]

cDCs: Conventional dendritic cells; ILC: Innate lymphoid cell; MAIT: Mucosal-associated invariant T; NK: Natural killer cell; NKT: Natural killer T cell; TCR: T cell receptor; CD: Cluster of differentiation; IL: Interleukin; MCD: Methionine- and choline-deficient; MASH: Metabolic dysfunction-associated steatohepatitis; XCR: X-C motif chemokine receptor; CXCR: C-X-C motif chemokine receptor.

Table 2 Clinical trials of metabolic dysfunction-associated steatotic liver disease treatments

Treatments	Drugs	Trials	Phases	Functions	Ref.
THR-β agonist	HSK31679	NCT05531097	1	Ameliorate diet-induced MASH by modulating gut microbiota and peripheral dendritic cells and macrophages	Zhang et al[94]
THR-β agonist	MGL-3196 (resmetirom)	NCT03900429	3	Treatment of resmetirom at a dose of 80 mg or 100 mg, once daily for 52 weeks, can improve liver fibrosis and reduce low-density lipoprotein cholesterol level from the baseline	Harrison et al[95]
THR-β agonist	TERN-501	NCT05415722	2	Reduce liver fat content compared to placebo in a dose-dependent manner	Noureddin et al[96]
Anti-human CCL24 monoclonal antibody	CM-101	NCT06044467	1	It can reduce serum levels of inflammatory and fibrotic biomarkers in patients with MASLD	Mor et al[99]
		NCT06037577	1
		NCT06025851	1
A long-acting fibroblast growth factor 21 analogue	Efimosfermin alfa	NCT04880031	2	Reduce hepatic glycogen storage, attenuate lipid accumulation, ameliorate fibrosis, and suppress immune response	Tang and Borlak[100]; Loomba et al[101]
Farnesoid X receptor agonist	Vonafexor (EYP001a)	NCT03812029	2	Reduce body weight, liver fat, and biomarker enzymes in patients with suspected fibrotic MASH	Ratziu et al[104]
PPAR agonist	Lanifibranor	NCT03459079	2	It significantly improved hepatic insulin sensitivity and reduced intrahepatic triglyceride content	Barb et al[109]
PPARα agonist	Pemafibrate	NCT03350165	2	Decrease levels of low-density lipoprotein cholesterol, non-HDL-C, and apolipoprotein B from the baselines in patients with MASLD	le Roux et al[112]
		NCT05923281	3
A dual agonist of glucagon receptor and glucagon-like peptide-1 receptor	Survodutide	NCT04771273	2	Reduce liver fat content and improve liver fibrosis in patients with MASH	Sanyal et al[113]
Free fatty acid receptor 1 and 4 agonist	Icosabutate (NST-4016)	NCT04052516	2	Reduce liver injury biomarkers and decrease liver inflammation and fibrosis in patients with MASH and mild to severe fibrosis	Harrison et al[114]

THR-β: Thyroid hormone receptor-β; CCL24: C-C motif chemokine ligand 24; PPAR: Peroxisome proliferator-activated receptor; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease; HDL-C: High-density lipoprotein cholesterol.