Fibrosis has a broad definition and can occur in various organs, including the liver, kidneys, pancreas, spleen, lungs, as well as the cardiovascular system, nervous system, and even organs like the eyeball. Some scholars consider scar formation in the epidermis as a manifestation of fibrosis. Scar formation causes a certain degree of functional loss in epidermal tissue: when it occurs in areas where hair grows, it can lead to hair loss; when it appears on the face, hands, or feet, it affects appearance, thereby reducing the patient’s self-confidence.
When fibrosis occurs in the liver, due to individual differences and varying causes of scarring, long-term stimulation by inflammatory responses eventually leads to local fibrous hyperplasia in the liver, forming calcified foci or fibrous foci. This is a compensatory response during the healing process of persistent liver damage. The activation of hepatic stellate cells (HSCs) significantly increases the secretion of extracellular matrix (ECM); the excessive proliferation and abnormal deposition of ECM ultimately result in liver fibrosis. This fibrotic process can cause severe liver dysfunction, such as malnutrition, decreased detoxification capacity, and hormonal insufficiency, and may even gradually develop into liver cirrhosis or liver cancer [2]. Another example is intra-abdominal fibrosis, which can impair the function of intramural ganglia, thereby affecting the normal function of internal organs—for instance, restricting the normal peristalsis of the gastrointestinal tract.
Currently, common drugs for treating epidermal scars include compound heparin sodium and allantoin gel, Kelo-Cote, etc. [3]. For the treatment of visceral scar formation and conjunctival fibrosis, drugs such as 5-fluorouracil, L-aspartic acid, or hormonal agents are also used. However, due to individual differences, these treatment regimens may cause severe adverse reactions such as myelosuppression and peripheral venous sclerosis.
Benefiting from the excellent performance of biological agents in terms of safety and efficacy in recent years, researchers have gradually shifted their focus to the field of biological agents. In the process of tissue fibrosis and scar formation, transforming growth factor-β1 (TGF-β1) plays a crucial role. Two subtypes of its receptors (TGF-β receptors, TβRs)—TβR1 and TβR2—are both involved in the activation of the TGF-β/Smad signaling pathway, which further promotes collagen secretion, ultimately leading to tissue fibrosis and scar formation. Therefore, blocking this signaling pathway holds significant scientific research value in addressing fibrosis and scarring.
Schematic Diagram of the Signaling Pathway (TGF-Smad) Inducing Scar Formation (Source: Internet)
As early as 2009, Chinese researchers significantly inhibited the expression level of TGF-β1 through TGF-β1 gene silencing, thereby reducing the levels of IL-1 and TNF-α to achieve the goal of anti-tissue fibrosis [4].
In 2021, researchers from Guangdong Pharmaceutical University successfully obtained the antigen peptide of the ligand-binding site of TβR2 based on the ligand-receptor interaction interface targeting strategy of transforming growth factor-β1. Using this antigen peptide, they screened two nanobodies targeting TβR2—TβR2-Nb17 and TβR2-Nb21—via phage display technology, further exploring nanobody-based drugs for anti-fibrosis and anti-scar formation. The study found that when the nanobody TβR2-Nb17 binds to fibroblasts, it can block the proliferation and migration of fibroblasts and reduce the expression of type I/III collagen. This research clearly demonstrates that inhibiting the activation of the TβR signaling pathway can effectively block the occurrence of scarring and tissue fibrosis.
Recently, researchers from the Department of Critical Care Medicine of Wuhan Fourth Hospital and the Department of Anesthesiology of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, reported that inhibiting miR-17 can activate autophagy, thereby suppressing the progression of TGF-β1-induced pulmonary fibrosis [5].
Research targeting TGF-β has laid a solid foundation for inhibiting or even reversing tissue fibrosis and scar formation. However, TGF-β not only inhibits the process of tissue fibrosis and scar formation but also plays an important role in promoting wound healing. Therefore, further research is still needed to address issues such as healing disorders and immune system dysregulation that may be caused by TβR inhibitors. We believe that in the future, there will be good news about the successful development of such antibody or nanobody drugs.
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