Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly rising in global prevalence and now stands as a leading cause of chronic liver disease worldwide. An evolving landscape in metabolic disease research has redefined this condition, previously classified under the umbrella of nonalcoholic fatty liver disease (NAFLD), to better capture the metabolic dysfunction that exacerbates disease progression from simple hepatic steatosis to steatohepatitis and fibrosis. Despite the widespread impact, current pharmacological interventions remain insufficient, underscoring a critical need for innovative therapeutic strategies grounded in molecular understanding.
In recent years, secreted proteins have emerged as key players in the pathogenesis and potential treatment of MASLD. These proteins, secreted into the extracellular space, engage in complex autocrine, paracrine, and endocrine signaling to modulate cellular metabolism, inflammation, and tissue remodeling. Their multifaceted roles offer unique opportunities to intervene at various stages of MASLD progression, ranging from lipid accumulation to fibrotic remodeling. Current research efforts focus on elucidating the mechanistic pathways these proteins engage, aiming to exploit their signaling properties therapeutically.
Among the myriad secreted proteins implicated in MASLD, the orosomucoid (ORM) family, especially ORM1, has captured considerable attention. ORM1 expression in extrahepatic tissues appears to mediate systemic metabolic regulation, offering hepatoprotective effects by mitigating steatosis and inflammation. Dysregulation of ORM1 correlates strongly with metabolic derangements and liver injury in MASLD, suggesting that targeted modulation of this protein could recalibrate metabolic homeostasis and decrease disease severity. This concept opens avenues for novel ORM-based therapeutics designed to harness its regulatory effects.
Matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) are also central to fibrogenesis and inflammation in MASLD. Elevated SPARC expression is consistently linked with enhanced extracellular matrix deposition and inflammatory signaling within the hepatic microenvironment, accelerating fibrosis and functional deterioration. Intervening in SPARC-mediated pathways may thus curb the fibrotic cascade, presenting a promising target for halting or reversing disease progression in advanced MASLD stages.
Another pivotal class of secreted proteins relevant to MASLD is the neuregulin (Nrg) family. Neuregulin 4 (Nrg4), an adipokine released predominantly by brown adipose tissue, exerts profound protective effects against hepatic steatosis and inflammatory infiltration. Mechanistically, Nrg4 dampens de novo lipogenesis and stimulates the ErbB4/AKT signaling axis, orchestrating metabolic reprogramming within hepatocytes that favors lipid clearance and anti-inflammatory states. The therapeutic efficacy of Nrg4 analogs is currently under active exploration, as their modulation may attenuate disease progression and improve liver function.
Growth differentiation factors (GDFs), notably GDF15 and GDF10, contribute to hepatic metabolic regulation by inhibiting lipogenesis and enhancing oxidative metabolism. Their expression and secretion are tightly regulated under metabolic stress, and experimental models reveal their capacity to protect against lipid-induced liver injury. Although the translational leap from preclinical findings to clinical application remains complex, GDFs represent attractive molecular targets with hepatoprotective promise grounded in their dual metabolic and anti-inflammatory capabilities.
Integral to the immune-metabolic interface, interleukin-22 (IL-22) has garnered considerable attention for its multi-modal hepatoprotective functions. IL-22 modulates inflammatory cascades, reduces hepatocyte lipid burden, and impedes fibrotic signaling pathways, positioning it as a powerful biological agent against MASLD and metabolic dysfunction-associated steatohepatitis (MASH). Clinical trials employing recombinant IL-22 analogs report encouraging outcomes, highlighting reduced hepatic steatosis and fibrosis markers, which advocates for further development of IL-22-based interventions.
Parallel to cytokine modalities, fibroblast growth factors (FGFs)—especially FGF21 and engineered analogs of FGF19—demonstrate significant metabolic benefits in MASLD patient cohorts. These factors act pleiotropically, orchestrating lipid metabolism, glucose homeostasis, and energy expenditure through receptor-mediated signaling cascades. Clinical trials have showcased their ability to reduce hepatic fat content and fibrotic progression, affirming their therapeutic value and informing the design of next-generation biotherapeutics to combat metabolic liver diseases.
Bone morphogenic proteins (BMPs) add yet another layer of complexity to MASLD pathobiology. BMP4, BMP6, and BMP7 exhibit protective properties by modulating lipid metabolism and inflammatory processes, offering anti-fibrotic benefits. Conversely, BMP8B and BMP9 demonstrate more ambiguous roles, sometimes exacerbating disease phenotypes. Clarifying these divergent effects is paramount for fully harnessing BMP signaling in the clinical management of MASLD, necessitating deeper mechanistic studies and translational research.
Emerging actors such as Isthmin-1 (Ism1) and mesencephalic astrocyte-derived neurotrophic factor (MANF) enhance our understanding of the intricate metabolic networks influencing MASLD progression. Ism1 promotes adipocyte glucose uptake and inhibits hepatic lipid synthesis, effectively rebuffing steatotic changes. MANF, through its endoplasmic reticulum stress-modulating properties, suppresses lipogenesis and attenuates fibrogenesis, indicating promising roles as therapeutic adjuncts or synergistic agents in treatment regimens aimed at metabolic and fibrotic sequelae.
The promise of secreted protein-based therapies in MASLD is not without challenges. Translational hurdles include optimizing dosage to maximize beneficial hepatic and extrahepatic effects while minimizing adverse outcomes, addressing the heterogeneity of patient phenotypes, and overcoming limitations intrinsic to current animal models that insufficiently recapitulate human disease complexity. Innovative bioengineering approaches, including protein engineering and targeted delivery systems, are being actively pursued to overcome these barriers.
Future directions pivot on integrating molecular insights with clinical realities to establish secreted proteins as viable therapeutic agents. Precision medicine approaches that stratify MASLD patients based on molecular and metabolic profiles will improve therapeutic outcomes by tailoring interventions. Furthermore, multi-omics technologies and advanced in vitro models, such as organoids and humanized liver systems, are accelerating the discovery pipeline, ensuring that candidate secreted proteins possess both mechanistic validity and translational relevance.
The comprehensive review titled “Exploring Secreted Proteins as Therapeutic Targets for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)” published in Protein & Cell on April 17, 2025, epitomizes this new frontier in hepatic research. It collates experimental insights surrounding secreted proteins and underscores their multifaceted roles in MASLD pathophysiology. By bridging bench findings and clinical prospects, this body of work charts a path toward novel biological therapies that could transform the therapeutic landscape for millions suffering from metabolic liver diseases.
The evolving understanding of secreted proteins underscores a paradigm shift from symptom management to targeted molecular therapy. Their ability to influence diverse biological processes integral to MASLD—from lipid metabolism and inflammation to fibrogenesis—positions them at the forefront of innovative treatment development. Continued multidisciplinary collaboration between basic scientists, clinicians, and pharmacologists will be essential to translate these promising candidates into effective, safe, and personalized therapies.
In summary, secreted proteins offer a vibrant and promising frontier for therapeutic innovation in MASLD. By harnessing their intrinsic signaling capacities, modulating metabolic dysfunction becomes a feasible goal, offering hope for an otherwise difficult-to-treat condition. The future of MASLD treatment lies in these molecular emissaries as we inch closer to a precision medicine era, transforming care paradigms and improving lives.
Subject of Research: Not applicable
Article Title: Secreted proteins in treating metabolic dysfunction-associated steatotic liver disease: from bench towards bedside
News Publication Date: April 17, 2025
Web References: http://dx.doi.org/10.1093/procel/pwaf027
Image Credits: Yeping Huang, Bin Liu, Cheng Hu, Yan Lu
Keywords: Cells
