ACVR1C/ALK7: An Emerging Target in Metabolic Diseases and Cancer Therapy

1. Research Background and Biomedical Significance of ACVR1C/ALK7

2. Molecular Characteristics, Structural Basis, and Ligand Recognition of ACVR1C/ALK7

3. ACVR1C/ALK7-Mediated Signal Transduction Pathways

4. The Role of ACVR1C/ALK7 in Disease Pathogenesis and Progression

5. Latest Research Progress on ACVR1C/ALK7-Targeting Drugs

1. Research Background and Biomedical Significance of ACVR1C/ALK7

ACVR1C (Activin receptor-like kinase 7, ALK7) is a type I receptor member of the TGF-β superfamily, possessing a typical receptor serine/threonine kinase domain and a GS regulatory region. Its function relies on forming complexes with type II receptors to mediate downstream signaling cascades. Early cloning and expression profiling studies revealed that ACVR1C exhibits significant spatiotemporal specificity in embryonic development and adult tissues, providing foundational evidence for its roles in developmental regulation and adult tissue homeostasis. Although its kinase core is highly conserved with ALK4/ALK5, minor differences in the extracellular domain significantly affect ligand affinity and signal output strength, endowing ACVR1C with functional uniqueness.

At the signal transduction level, ACVR1C primarily activates the canonical TGF-β-like pathway mediated by Smad2/3, while concurrently triggering non-canonical pathways such as MAPK and PI3K/AKT under specific cellular conditions, thereby achieving integrated regulation of cell proliferation, differentiation, migration, and metabolism. Growing evidence indicates that its signal output highly depends on ligand type, receptor complex composition, and intracellular regulatory factors (such as I-Smads and E3 ubiquitin ligases), providing a mechanistic basis for explaining the opposing effects of ACVR1C in different physiological and pathological contexts. However, current research predominantly relies on in vitro overexpression systems or broad-spectrum inhibitors, limiting the precise elucidation of ACVR1C's intrinsic functions and its interplay with other type I receptors, highlighting the necessity for developing selective tools and conditional in vivo models.

Functional studies have closely linked ACVR1C to embryonic development, adipose tissue homeostasis, and energy metabolism. Gene knockout and developmental models suggest its involvement in stem cell fate determination and organogenesis. In adult metabolic tissues, ACVR1C influences insulin sensitivity and energy balance by inhibiting preadipocyte proliferation and promoting differentiation, making it a focal point in obesity and type 2 diabetes research. Conversely, in cancer and fibrosis studies, the role of ACVR1C exhibits a clear duality: it can exert inhibitory effects in some tumor contexts while promoting invasion and migration in specific microenvironments, reflecting the decisive influence of cellular context and ligand repertoire on its signal output. Due to limited human genetic and clinical association evidence, establishing a causal relationship between ACVR1C and disease phenotypes at the genetic level remains a major challenge in the field.

2. Molecular Characteristics, Structural Basis, and Ligand Recognition of ACVR1C/ALK7

2.1 Gene Structure, Protein Conformation, and Tissue Expression Characteristics

ACVR1C belongs to the TGF-β superfamily type I receptors, comprising an extracellular ligand-binding domain, a single transmembrane helix, and intracellular GS and kinase domains. It was initially cloned as an orphan receptor and later confirmed as a type I receptor for Nodal and Activin-like ligands ^[1]. Structural and binding studies indicate that Nodal forms a multimolecular complex with Cripto and ALK4/ALK7, where key amino acid residues determine ligand selectivity ^[2]. Notably, Activin-like ligands exhibit dual specificity: primarily activating Smad2/3 via ALK4/ALK7, but some dimers can also activate Smad1/5 via ALK2, suggesting that ligand composition and receptor pairing jointly determine signaling branch selection ^[3].

Transcriptomic and molecular studies consistently show that ACVR1C is highly enriched in white and brown adipose tissues and significantly upregulated during the late stages of adipocyte differentiation ^[4]. Human adipose tissue studies further confirm that its expression is negatively correlated with obesity and closely related to glycolipid metabolism indicators, supporting the role of the Activin B–ALK7 axis in adipose tissue homeostasis regulation ^[5]. Furthermore, ACVR1C is also expressed in the nervous system and pancreatic β-cells, with various splice variants exhibiting differences in signaling capacity ^[6]. For example, Alk7-v3 cannot effectively transduce Nodal-Cripto signals, suggesting that transcriptional variants can reshape signal output without altering receptor expression. Its expression can also be regulated by metabolic stimuli; for instance, β3-adrenergic agonists downregulate ALK7 expression in brown adipose tissue, reflecting its cross-regulation with sympathetic-metabolic pathways ^[6]. Recent transcriptomic studies have also linked ACVR1C to neuroendocrine development, showing that it inhibits Mkrn3 expression via Smad2/3-mediated chromatin regulation, thereby affecting puberty onset ^[7].

2.2 Key Ligand Recognition and Receptor Activation Mechanisms

At the ligand level, Activin E (INHBE) is considered a crucial functional ligand for ACVR1C, activating the Smad2/3 pathway via this receptor and regulating energy metabolism-related gene expression ^[9][10]. Pharmacological blockade experiments show that the small-molecule inhibitor SB431542 inhibits Activin E-induced Smad2/3 phosphorylation and downstream transcriptional activation, supporting its signaling through ALK7 ^[10]. Embryonic model studies indicate that Nodal signaling primarily relies on ALK4 in early developmental stages, while ALK7 is not essential for embryogenesis and is more likely to perform tissue-specific or ligand-specific functions ^[11-13].

Functionally, the role of the Activin E–ACVR1C axis in metabolic regulation exhibits phenotypic disparities. On one hand, mouse in vivo studies suggest this pathway inhibits lipolysis, promotes fat storage, and suppresses PPARγ-related genes, potentially increasing metabolic risk ^[9]; on the other hand, in vitro studies on brown/beige adipocytes show Activin E can upregulate Ucp1 and Fgf21 via ALK7/Smad2/3, indicating its role in promoting thermogenesis and energy expenditure in specific lineages ^[10]. These discrepancies can be explained by differences in research models, cell types, dosages, timing, and receptor microenvironment, emphasizing the critical roles of signal bias and chromatin context in determining transcriptional outcomes. Due to the lack of systematic affinity measurements and high-resolution structural data, the molecular basis of ligand-receptor selectivity remains to be elucidated ^[11].

3. ACVR1C/ALK7-Mediated Signal Transduction Pathways

ACVR1C/ALK7, as a key node in the TGF-β superfamily signaling network, converts extracellular ligand stimuli into multi-layered intracellular responses. Its signal output includes both the classic transcriptional regulatory axis centered on Smad2/3 and various non-canonical signaling branches. The division of labor among different pathways in terms of timescale, spatial localization, and biological effects results in significant context-dependent functionality for ACVR1C.

3.1 The Smad2/3-Dependent Canonical Signaling Pathway

In the classic model, ligand binding promotes the formation of a complex between the type II receptor and ACVR1C. The type II receptor phosphorylates the GS region of ACVR1C, thereby activating its kinase activity and recruiting Smad2/3. Phosphorylated Smad2/3 forms a complex with co-Smad4, translocates into the nucleus, and regulates target gene transcription ^[14]. This axis plays a central role in adipocyte differentiation, pancreatic β-cell function, and fate determination in various tumor cells.

In tumor models, ACVR1C-Smad2 signaling has been shown to promote tumor cell invasion and growth in specific contexts. For example, in retinoblastoma, upregulated ACVR1C expression accompanies enhanced Smad2 activity, and inhibiting this pathway significantly reduces invasion and survival capacity, while the role of Smad3 is relatively limited ^[16]. These results suggest that despite high structural similarity, Smad2 and Smad3 may bear different functional weights in ACVR1C signal output, with differences potentially determined by receptor-ligand combinations and nuclear co-factors ^[15].

3.2 Non-Canonical Signaling Pathways and Signal Bias

Besides the canonical Smad pathway, ACVR1C can also mediate non-canonical signals via β-arrestin, Ral GTPase, etc. Related studies show that Nodal-ALK7 signaling can form stable complexes in the cytoplasm, regulating receptor internalization, ERK1/2 activation, and cytoskeleton remodeling, thereby rapidly affecting cell migration and invasion behavior ^[17]. In pancreatic cancer models, ALK7 promotes basement membrane disruption and tumor cell intravasation via the β-catenin/MMP axis, emphasizing the role of its non-Smad branches in the metastasis process ^[18].

Furthermore, ACVR1C can regulate macrophage and vascular smooth muscle cell phenotypes by inhibiting PPARγ expression, promoting inflammatory responses and vascular remodeling ^[19][20]. These findings indicate that ACVR1C's signal output is not a single pathway but is shaped by multiple parallel pathways, with bias depending on cell type, ligand concentration, and receptor microenvironment.

4. The Role of ACVR1C/ALK7 in Disease Pathogenesis and Progression

4.1 Tumor Initiation, Progression, and Metastasis

In various solid tumors, ACVR1C can induce cell apoptosis and inhibit tumor dissemination via Smad2/3-mediated transcriptional programs, regarded as an intrinsic tissue homeostasis barrier [23],[24]. Clinical sample analyses show that reduced ACVR1C expression is often associated with poor prognosis, such as in gallbladder cancer and breast cancer ^[25-28].

However, in contexts like colorectal cancer, retinoblastoma, and pancreatic ductal adenocarcinoma, ACVR1C can be repurposed by tumor cells to promote EMT, stemness maintenance, and metastasis through autocrine or paracrine loops ^[29-32]. These contradictory phenomena highlight the highly context-dependent nature of ACVR1C in cancer, with its function contingent upon the ligand repertoire, signaling pathway bias, and tumor microenvironment state.

4.2 Metabolic Diseases and Adipose Tissue Function

Population genetics studies provide strong evidence for ACVR1C's causal role in human body fat distribution. Rare variant analysis from the UK Biobank shows that loss-of-function of ACVR1C is associated with more favorable fat distribution and lipid profiles ^[38]. Functional studies further indicate that ACVR1C affects fat storage and insulin sensitivity by inhibiting lipolysis and regulating PPARγ signaling ^[21].

It is important to note that ACVR1C is also involved in regulating insulin gene expression and cell survival in pancreatic β-cells, and excessive inhibition of this pathway may pose risks to islet function ^[42-44]. Therefore, its development as a therapeutic target for metabolic diseases requires emphasis on tissue specificity and safety window evaluation.

4.3 Cardiovascular, Reproductive, and Neurological Diseases

In the cardiovascular system, ACVR1C can inhibit pathological cardiac hypertrophy under pressure overload conditions, while its activation in a diabetic context may promote myocardial apoptosis and fibrosis ^[45-47]. In pregnancy-related diseases, Nodal-ALK7 signaling inhibits trophoblast cell invasion and is believed to be associated with preeclampsia occurrence ^[48][49].

In the nervous system, ACVR1C is involved in post-ischemic neuroprotection and also plays a role in synaptic plasticity and memory formation ^[8], suggesting its potential for different intervention values in acute injury versus chronic neurodegenerative changes.

5. Latest Research Progress on ACVR1C/ALK7-Targeting Drugs

ACVR1C/ALK7, as an important signaling receptor in the TGF-β superfamily, plays key roles in various physiological and pathological processes such as metabolic regulation and tumor progression, and has recently become an emerging therapeutic target. Current drug development targeting ACVR1C mainly focuses on different strategies including siRNA, small-molecule inhibitors, and monoclonal antibodies, covering diseases such as obesity, cancer, diabetic nephropathy, and SARS-CoV-2 infection. Some pipelines under investigation are summarized in the table below:

Drug	Mechanism of Action	Drug Type	Indication Under Investigation	Research Institution	Highest R&D Phase
ARO-ALK7	ALK7 Inhibitor	siRNA	Obesity	Arrowhead Pharmaceuticals, Inc.	Clinical I/II
A-83-01	ALK4/5/7 Inhibitor	Small Molecule	Cancer	Japanese Foundation for Cancer Research	Preclinical
ALN-2232	ALK7 Inhibitor	siRNA	Obesity	Alnylam Pharmaceuticals, Inc.	Preclinical
SB-431542	ALK4/5/7 Inhibitor	Small Molecule	SARS-CoV-2 Infection	Indian Council of Medical Research	Preclinical
ALK7 siRNA (Shian Bio)	ALK7 Inhibitor	siRNA	Obesity	Suzhou Shian Biotechnology Co., Ltd.	Preclinical
ITI-8000	ALK7 Inhibitor	mAb (Monoclonal Antibody)	Cancer	Immunomic Therapeutics, Inc.	Preclinical
Protocatechuic Aldehyde	ALK7 Modulator	Small Molecule	Diabetic Ulcer	Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine	Preclinical
SB-505124	ALK4/5/7 Inhibitor	Small Molecule	\-	GSK Plc	Preclinical
SGB-ALK7	ALK7 Inhibitor	siRNA	Obesity	Suzhou SGB Pharmaceuticals Co., Ltd.	Preclinical

(Data as of December 26, 2025, sourced from Synapse)

6. ACVR1C/ALK7-Related Research Tools

ACVR1C/ALK7 is a crucial signaling node connecting developmental biology, metabolic regulation, and disease pathology. Its biological effects highly depend on cell type, ligand environment, and signal bias, which endows it with therapeutic potential but also increases translational difficulty. CUSABIO provides ACVR1C/ALK7 antibody products to support your related mechanism research and targeted drug development.

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