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Target: TGFB1


Research on TGFB1 (Transforming Growth Factor Beta 1)

1. Target Summary:

TGFB1, or Transforming Growth Factor Beta 1, is a multifunctional cytokine that plays a crucial role in regulating cell growth, differentiation, and immune responses. It is particularly known for its involvement in fibrosis, cancer progression, and tissue repair. TGFB1 is produced by various cell types, including platelets, macrophages, and fibroblasts, and it exerts its effects through binding to specific receptors, initiating a cascade of intracellular signaling pathways.

2. Mechanism:

TGFB1 primarily functions by binding to its receptors (TGFBR1 and TGFBR2), which activates the Smad signaling pathway. Upon receptor activation, Smad proteins (Smad2 and Smad3) are phosphorylated and form a complex with Smad4. This complex translocates to the nucleus, where it regulates the transcription of target genes involved in fibrosis, inflammation, and cell differentiation.
In the context of fibrosis, TGFB1 promotes the activation of fibroblasts into myofibroblasts, leading to increased production of extracellular matrix (ECM) components such as collagen. This process is crucial in wound healing but can lead to pathological fibrosis when dysregulated. TGFB1 also induces epithelial-to-mesenchymal transition (EMT), a process where epithelial cells lose their characteristics and gain migratory and invasive properties, contributing to cancer metastasis (PMID: 37532929, 38417530).
Additionally, TGFB1 modulates immune responses by promoting the differentiation of regulatory T cells (Tregs) and inhibiting the activity of cytotoxic T cells and natural killer (NK) cells, thereby creating an immunosuppressive tumor microenvironment (PMID: 38193973).

3. Approved Drugs:

Currently, there are no specific drugs approved solely for targeting TGFB1. However, several therapeutic strategies aim to inhibit TGFB1 signaling in various diseases, particularly in fibrosis and cancer. These include monoclonal antibodies against TGFB1 and small molecule inhibitors targeting the TGF-beta receptor pathways.

4. Hypotheses:

  1. TGFB1 as a Therapeutic Target: Inhibiting TGFB1 signaling may reduce fibrosis and improve tissue repair in chronic diseases such as liver fibrosis and pulmonary fibrosis (PMID: 37678798).
  2. Role in Cancer Progression: TGFB1 promotes EMT and immune evasion in tumors, suggesting that targeting TGFB1 could enhance the efficacy of immunotherapies and reduce metastasis (PMID: 38417530).
  3. Interaction with Other Pathways: TGFB1 may interact with other signaling pathways, such as the PI3K/Akt and MAPK pathways, to modulate cellular responses in cancer and fibrosis (PMID: 30081711).

5. Validation:

TGFB1 has been validated as a significant factor in various pathological conditions. Studies have shown that blocking TGFB1 signaling can ameliorate fibrosis in animal models and improve outcomes in patients with fibrotic diseases (PMID: 37678798, 16420505). Additionally, TGFB1 levels correlate with disease severity in conditions like chronic kidney disease and liver fibrosis, supporting its role as a biomarker for disease progression (PMID: 30853453).

6. Clinical Trials:

Numerous clinical trials are investigating the efficacy of TGFB1 inhibitors in treating fibrotic diseases and cancers. For example, trials are exploring the use of monoclonal antibodies targeting TGFB1 in patients with liver fibrosis and various cancers (PMID: 28287848, 29624476). These trials aim to assess the safety and effectiveness of these therapies in reducing fibrosis and improving patient outcomes.

7. Involved Pathways:

  • Smad Signaling Pathway: Central to TGFB1's action, mediating its effects on gene expression related to fibrosis and EMT.
  • PI3K/Akt Pathway: Interacts with TGFB1 signaling to regulate cell survival and proliferation.
  • MAPK Pathway: Involved in TGFB1-induced cellular responses, including inflammation and fibrosis.

8. Associated Genes:

  • TGFB1: The primary gene encoding the TGFB1 protein.
  • SMAD2/3: Key mediators of TGFB1 signaling.
  • COL1A1: A gene encoding collagen, a major component of the extracellular matrix influenced by TGFB1.
  • ACTA2: Associated with myofibroblast differentiation and fibrosis.

9. Target Expression:

TGFB1 is expressed in various tissues, including the liver, lungs, and kidneys, and its expression is often upregulated in fibrotic conditions and tumors. Elevated levels of TGFB1 are associated with poor prognosis in several cancers, indicating its role in disease progression (PMID: 37532929, 38417530).

10. Additional Context:

TGFB1's dual role as a promoter of fibrosis and a modulator of immune responses makes it a complex target for therapy. While inhibiting TGFB1 may alleviate fibrosis, it could also impair normal wound healing and immune responses, necessitating careful consideration in therapeutic strategies (PMID: 37678798, 16420505).

11. References:

  1. PMID: 37532929 - Pharmacological targeting of netrin-1 inhibits EMT in cancer.
  2. PMID: 38417530 - TGF-beta1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression.
  3. PMID: 37678798 - Hepatocyte FoxO1 Deficiency Protects From Liver Fibrosis.
  4. PMID: 16420505 - Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis.
  5. PMID: 30853453 - MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho.
  6. PMID: 29624476 - Immunotherapy in inflammatory bowel disease: Novel and emerging treatments.
This comprehensive overview of TGFB1 highlights its critical role in fibrosis and cancer, the mechanisms by which it operates, and the potential therapeutic strategies targeting its signaling pathways.