Liver immunology: Biological role and clinical significance

Table 1 Prospective directions of immunotherapy of metabolic dysfunction-associated steatotic liver disease

Therapeutic approach	Mechanism	Current state	Ref.
Anti-programmed cell death 1/programmed death-ligand 1 therapy	Inhibition of immune checkpoint	Early phase, mixed results	Lombardi et al[74], Jeong et al[184], Zhang et al[203], Pinto et al[204]
MSCs	Immunomodulatory, anti-inflammatory agent	Promising preclinical results. MSC heterogeneity and long-term safety issues remain serious obstacles	Moayedfard et al[157], Niu et al[205], Yang et al[206], Hu et al[207]
Extracellular vesicles	Modulation of the immune response	Promising preclinical results	Ipsen et al[208], Abreo Medina et al[209], Niu et al[205], Yang et al[206]
Probiotics (Lactobacillus plantarum, Bifidobacterium bifidum)	Modulation of intestinal microbiota, anti-inflammatory agent		Lu et al[210], Zhang et al[211], Wen et al[212], Tang et al[213]
Targeting cytokines (e.g., IL-17), IL-1β inhibitors tumor necrosis factor-alpha inhibitors nucleotide-binding and oligomerization domain-like receptor protein 3 inflammasome inhibition	Reducing inflammation	Preclinical studies have shown mixed results	Rafaqat et al[214], Paquissi et al[215], Kucsera et al[216], Duan et al[217], Bakhshi et al[218], Mridha et al[219]
Natural anti-inflammatory agents, astaxanthin. Apigenin, ginsenoside Rg1	Reducing inflammation	Preclinical studies have shown promising results	Lv et al[220], Yang et al[221], Xu et al[222]
Inhibition of apoptosis signal-regulating kinase 1 (selonsertib [GS-4997])	Reduction of inflammation and fibrosis	Patients with MASH may develop liver scarring (fibrosis), including cirrhosis, which increases the risk of liver failure and liver cancer	Harrison et al[223], Loomba et al[224]
Caspase inhibition (Emricasan [IDN-6556])	Reduced hepatocyte apoptosis in a mouse model of MASH liver injury and fibrosis are suppressed by inhibiting hepatocyte apoptosis.	Emricasan treatment did not improve liver histologic pattern in patients with MASH fibrosis. Emricasan administration was not associated with improved hepatic venous pressure gradient or clinical outcomes in patients with MASH-related cirrhosis and severe portal hypertension	Harrison et al[225], Barreyro et al[226], Frenette et al[227], Garcia-Tsao et al[228]
FXR agonists	Regulation of bile acid synthesis, lipid metabolism, glucose homeostasis and inflammation	FXR agonists have shown promising results	Gandhe et al[190], Tang et al[191], Clifford et al[192], Adorini et al[193], Xu et al[194]
FGF21 analogs	Regulation of glucose and lipid metabolism, insulin sensitivity	FGF21 analogs have shown promising results	Su et al[195], Harrison et al[196], Falamarzi et al[197], Carbonetti et al[198], Corbee et al[199], Raptis et al[200], Chui et al[201], Theofilis et al[202]

FGF21: Fibroblast growth factor 21; FXR: Farnesoid X receptor; IL: Interleukin; MASH: Metabolic dysfunction-associated steatohepatitis; MSCs: Mesenchymal stem cells.