Han Hyeong-Jun, Kim Hyunyoung
Division of Intractable Diseases, Department of Chronic Diseases Convergence Research, Korea National Institute of Health, Cheongju, 28160, Republic of Korea.
National Stem Cell Bank of Korea, Korea National Institute of Health, Cheongju, 28160, Republic of Korea.
Biochem Biophys Rep. 2025 Aug 11;43:102191. doi: 10.1016/j.bbrep.2025.102191. eCollection 2025 Sep.
Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. Excessive deposition of extracellular matrix (ECM) results in fibrotic remodeling, alveolar destruction, and irreversible lung dysfunction. In addition to myofibroblast activation and ECM deposition, repetitive lung epithelial cell damage and reprogramming areconsidered to be closely involved in IPF pathogenesis. Transforming growth factor (TGF)-β1 plays an important role in IPF and cancer; it is a major pro-fibrotic cytokine, and is a potential target for treating fibrotic diseases.TGF-β1 binds to TGF-βRII, phosphorylating TGF-βRI, and enhances ECM expression via the suppressor of mothers against decapentaplegic (SMAD) phosphorylation signaling pathway. Current medical interventions for IPF are predominantly anti-fibrotic medications such as pirfenidone and nintedanib, which are effective in delaying lung function deterioration, reducing acute symptom exacerbations, and increasing overall life expectancy. However, these pharmaceutical agents cannot repair fibrotic pulmonary tissues or impede disease progression. To bridge this gap, we constructed a model of TGF-β1-induced fibrosis and screened for potential drugs. From 320 anti-fibrotic drugs, 9 hits were found in the TGF-β1-induced fibrosis model, and after validation, the final 7 hits were identified as TGF-β1 inhibitors. All the 7 hits were confirmed as TGF-βRI inhibitors, which showed that the model could quickly and easily discover new compounds that can act as TGF-β1 inhibitors. This study is significantbecausewe useda 3D model to swiftly and precisely identify TGF-β1 inhibitors, potentially accelerating the clinical translation of TGF-β1-targeted therapies for fibrotic diseases.
特发性肺纤维化（IPF）是一种慢性、进行性纤维化肺病的典型代表。细胞外基质（ECM）的过度沉积导致纤维化重塑、肺泡破坏和不可逆的肺功能障碍。除了肌成纤维细胞活化和ECM沉积外，重复性肺上皮细胞损伤和重编程也被认为与IPF发病机制密切相关。转化生长因子（TGF）-β1在IPF和癌症中起重要作用；它是一种主要的促纤维化细胞因子，是治疗纤维化疾病的潜在靶点。TGF-β1与TGF-βRII结合，使TGF-βRI磷酸化，并通过抗五聚体蛋白母抑制因子（SMAD）磷酸化信号通路增强ECM表达。目前针对IPF的医学干预主要是抗纤维化药物，如吡非尼酮和尼达尼布，它们在延缓肺功能恶化、减少急性症状加重和延长总体预期寿命方面有效。然而，这些药物无法修复纤维化肺组织或阻止疾病进展。为了弥补这一差距，我们构建了TGF-β1诱导的纤维化模型并筛选潜在药物。在320种抗纤维化药物中，在TGF-β1诱导的纤维化模型中发现了9种有效药物，经过验证，最终确定了7种有效药物为TGF-β1抑制剂。所有7种有效药物均被确认为TGF-βRI抑制剂，这表明该模型可以快速、轻松地发现可作为TGF-β1抑制剂的新化合物。这项研究具有重要意义，因为我们使用三维模型快速、准确地鉴定了TGF-β1抑制剂，可能会加速针对纤维化疾病的TGF-β1靶向治疗的临床转化。
