SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as p21WAF1 and p15INK4b through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of SMAD4 could be related to tumorigenesis or malignancy progression. However, in some cancer types, SMAD4 is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced p15INK4b mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis.

Background: A subset of patients with chronic dyspepsia exhibits palpable upper abdominal hardness and systemic symptoms like headache, chest discomfort, neck/shoulder stiffness, fatigue, and depression. In traditional Korean medicine (TKM), this symptom complex is referred to as Damjeok syndrome (痰积症候群, DJS). Although DJS is frequently observed in TKM practice, it lacks a clear case definition and biological mechanism, limiting its integration in gastroenterology research and evidence-based practice. Clarifying its clinical and biological features is essential to understand its pathophysiology and clinical significance. Methods: This case–control study aimed to characterize DJS by comparing 16 female patients diagnosed with DJS and 15 age-matched healthy females as controls. A female-only cohort was selected to reflect the higher prevalence of chronic dyspepsia in women and reduce biological variability. Clinical characteristics and potential DJS-specific biomarkers were evaluated through complete blood count (CBC), serum biochemical tests, heart rate variability (HRV) for autonomic function, and plasma 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite linked to gastrointestinal motility and autonomic regulation. Results: The DJS group had a mean disease duration of 58.0 ± 46.2 months, with epigastric fullness and underlying abdominal hardness as primary complaints. Postprandial distress syndrome (PDS) was the most common (43.8%) dyspepsia subtype, often combined with epigastric pain syndrome (EPS). Extra-gastrointestinal symptoms such as headache/fatigue (87.5%) and anxiety/depression (81.3%) were highly prevalent. Neutrophil counts were significantly lower in the DJS group (p = 0.01), while other hematological or biochemical markers showed no differences (p > 0.1). HRV analysis revealed decreased parasympathetic activity (RMSSD and HF, p < 0.1), and plasma 5-HIAA levels were significantly elevated compared to healthy controls (p = 0.01). Conclusions: DJS aligns with functional gastrointestinal disorders (FGIDs), sharing psychosomatic symptoms and reduced parasympathetic activity, suggesting gut–brain axis dysregulation. However, distinct features like palpable upper abdominal hardness and elevated plasma 5-HIAA levels indicate that DJS may represent a unique subtype within the category of FGIDs. These findings highlight the need for larger, well-designed studies to further elucidate the pathophysiology of DJS.