Secreted proteins in treating metabolic dysfunction-associated steatotic liver disease: from bench towards bedside

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global epidemic, yet effective pharmacological treatments remain limited. Secreted proteins play diverse roles in regulating glucose and lipid metabolism, and their dysregulation is implicated in the development of various metabolic diseases, including MASLD. Therefore, targeting secreted proteins and modulating associated signaling pathways represents a promising therapeutic strategy for MASLD. In this review, we summarize recent findings on the roles of emerging families of secreted proteins in MASLD and related metabolic disorders. These include the orosomucoid (ORM) family, secreted acidic cysteine rich glycoprotein (SPARC) family, neuregulin (Nrg) family, growth differentiation factor (GDF) family, interleukin (IL) family, fibroblast growth factor (FGF) family, bone morphogenic protein (BMP) family, as well as isthmin-1 (Ism1) and mesencephalic astrocyte-derived neurotrophic factor (MANF). The review highlights their impact on glucose and lipid metabolism and discusses the clinical potential of targeting these secreted proteins as a therapeutic approach for MASLD.

Keywords: clinical application; hepatic lipid metabolism; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; secreted proteins.

Figure 1.

Roles of secreted proteins in the development and progression of metabolic dysfunction-associated steatotic liver disease. ORM2, Nrg4, GDF10, Ism1, MANF, IL-22, FGF21, FGF19, IL-18, GDF15, FGF1, BMP4, BMP7, BMP9, Nrg1, and ORM1 can ameliorate hepatic steatosis, while BMP8B and BMP2 facilitate it. ORM2, Nrg4, GDF10, MANF, IL-22, GDF15, FGF21, FGF19, FGF1, BMP4, BMP6, ORM1, and IL-18 can alleviate MASH, whereas SPARC, SPARCL1, BMP8B, BMP9, and GDF3 aggravate it. Nrg4 suppresses the progression from MASH to hepatocellular carcinoma, whereas MANF inhibits hepatocellular carcinoma development. BAT, brown adipose tissue; ER, endoplasmic reticulum; FA, fatty acid; HSCs, hepatic stellate cells; KCs, Kupffer cells; WAT, white adipose tissue.

Figure 2.

Secreted proteins as therapeutic targets for treating MASLD and MASH: preclinical and clinical evidence. Preclinical studies show that recombinant proteins like ORM2, ORM2-IgG Fc, IL-22, IL-22-IgG Fc, Ism1, Nrg4, GDF15, MANF, and FGF1, can potentially relieve hepatic steatosis. Moreover, ORM2, Nrg4, GDF15, MANF, FGF1, and SPARCL1 neutralizing antibody can attenuate MASH. In addition, Nrg4 can suppress the progression from MASH to hepatocellular carcinoma, and MANF can inhibit the development of hepatocellular carcinoma. Clinical trials reveal that the FGF19 analogue aldafermin can decrease liver fat content and fibrosis in MASH patients. The FGF21 analogue pegozafermin and efruxifermin can reduce liver fat, fibrosis, and injury in patients with severe hypertriglyceridemia, MASH, and liver fibrosis. Efruxifermin combined with GLP-1 receptor agonist therapy can reduce liver fat and fibrosis in MASH patients with T2DM. Additionally, the FGF19 analogue aldafermin and the FGF21 analogue efruxifermin can improve liver fibrosis and liver injury in patients with MASH-compensated cirrhosis. GLP-1 RA, GLP-1 receptor agonist; r, recombinant; SHTG, severe hypertriglyceridemia.