Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), encompasses a spectrum of conditions ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Despite its prevalence, effective pharmacological treatments remain limited. Secreted proteins, known for their roles in autocrine, paracrine, and endocrine signaling, offer promising therapeutic avenues. This review synthesizes recent research on the roles of secreted proteins in MASLD pathophysiology and their potential as therapeutic targets.
Key findings from the study include:

1. Orosomucoid (ORM) Family: ORM1 and ORM2 are implicated in metabolic regulation, with ORM1 showing protective effects against MASLD through extrahepatic tissues. Dysregulation of ORM1 is linked to MASLD-related disorders, highlighting its therapeutic potential.
2. SPARC Family: SPARC, a matricellular protein, is involved in fibrosis and inflammation in MASLD. Its upregulation is associated with liver injury and fibrosis, positioning it as a potential therapeutic target.
3. Neuregulin (Nrg) Family: Nrg4, an adipokine, alleviates hepatic steatosis and inflammation by suppressing de novo lipogenesis and activating ErbB4/AKT signaling. Its protective role in MASLD/MASH progression makes it a promising therapeutic candidate.
4. Growth Differentiation Factor (GDF) Family: GDF15 and GDF10 show hepatoprotective effects by inhibiting lipogenesis and promoting oxidative metabolism. Their potential as therapeutic targets is supported by preclinical studies, though clinical translation remains challenging.
5. Interleukin (IL) Family: IL-22 exhibits anti-steatotic, anti-inflammatory, and anti-fibrotic effects in the liver, making it a strong candidate for MASLD/MASH treatment. Clinical trials with recombinant IL-22 show promise in reducing hepatic steatosis and fibrosis.
6. Fibroblast Growth Factor (FGF) Family: FGF21 and FGF19 analogues demonstrate efficacy in reducing liver fat and fibrosis in MASLD patients. Their pleiotropic effects on lipid metabolism, glucose homeostasis, and energy expenditure make them attractive therapeutic options.
7. Bone Morphogenic Protein (BMP) Family: BMP4, BMP6, and BMP7 show protective effects against MASLD, while BMP8B and BMP9 have conflicting roles. Further research is needed to fully elucidate their mechanisms and therapeutic potential.
8. Isthmin-1 (Ism1) and MANF: Ism1 enhances adipocyte glucose uptake and suppresses hepatic lipid synthesis, while MANF suppresses lipogenesis and fibrosis. Their roles in metabolic regulation suggest potential as therapeutic targets for MASLD.

Secreted proteins represent a promising frontier in the development of novel therapies for MASLD. Their diverse roles in metabolic regulation, coupled with their dysregulation in MASLD, underscore their therapeutic potential. However, translating preclinical findings into effective clinical treatments remains challenging. Future research should focus on optimizing the beneficial effects of secreted proteins while minimizing risks, addressing heterogeneity in MASLD, and developing more clinically relevant animal models. The work entitled “ Exploring Secreted Proteins as Therapeutic Targets for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)” was published on Protein & Cell (published on Apr. 17, 2025).
DOI: 10.1093/procel/pwaf027