Bhardwaj Shivani, Gautam Rohit Kumar, Kushwaha Sapana
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226002, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Sarojini Nagar, Near CRPF Base Camp, Lucknow, Uttar Pradesh 226002, India.
Cytokine Growth Factor Rev. 2025 Aug 22. doi: 10.1016/j.cytogfr.2025.08.003.
Cellular senescence and the formation of fibrotic scarring are critical in the progression of chronic illnesses, such as pulmonary fibrosis (PF). In this context, the transforming growth factor-beta (TGF-β) pathway represents a central driver in orchestrating the pathological cascade. TGF-β governs cellular activities such as differentiation, apoptosis, and extracellular matrix (ECM) remodeling as a pleiotropic cytokine. In the lungs, dysregulated TGF-β signaling leads to cellular senescence and release of pro-inflammatory mediators, constituting the senescence-associated secretory phenotype (SASP). This reinforces a microenvironment conducive to fibroblast activation, prolonged myofibroblast retention, and accelerated aberrant ECM deposition, culminating in progressive tissue fibrosis. For instance, idiopathic pulmonary fibrosis (IPF) is marked by the buildup of senescent alveolar epithelial cells (AECs) that impair regular tissue repair and alter the microenvironment to promote fibrogenesis. TGF-β signaling is activated through SMAD-dependent (canonical) and SMAD-independent (non-canonical) pathways, each contributing to the persistence of activated fibroblasts, aberrant ECM accumulation, and irreversible tissue remodeling. The interdependence between senescence and TGF-β signaling perpetuates fibrotic injury and enhances susceptibility to future fibrotic insults. This review delves into understanding the molecular convergence of TGF-β signaling and cellular senescence in PF, highlighting key biomarkers and emerging therapeutic strategies. While several clinical trials evaluating TGF-β antagonists, small molecules, and cell-based therapies show considerable promise, challenges remain regarding their successful translation into effective, targeted treatments. Nevertheless, continued exploration of TGF-β's multifaceted role in fibrosis and senescence offers hope for developing innovative therapies for PF and other chronic fibrotic diseases.
细胞衰老和纤维化瘢痕形成在慢性疾病（如肺纤维化，PF）的进展中至关重要。在此背景下，转化生长因子-β（TGF-β）信号通路是协调病理级联反应的核心驱动因素。TGF-β作为一种多效性细胞因子，调控细胞分化、凋亡和细胞外基质（ECM）重塑等细胞活动。在肺部，TGF-β信号失调会导致细胞衰老和促炎介质释放，构成衰老相关分泌表型（SASP）。这强化了有利于成纤维细胞激活、肌成纤维细胞长期存留和加速异常ECM沉积的微环境，最终导致进行性组织纤维化。例如，特发性肺纤维化（IPF）的特征是衰老肺泡上皮细胞（AECs）的积累，这会损害正常组织修复并改变微环境以促进纤维化。TGF-β信号通过SMAD依赖（经典）和SMAD非依赖（非经典）途径激活, 每条途径都促成了活化成纤维细胞的持续存在、异常ECM积累和不可逆的组织重塑。衰老与TGF-β信号之间的相互依存关系使纤维化损伤持续存在，并增强对未来纤维化损伤的易感性。本综述深入探讨了PF中TGF-β信号与细胞衰老的分子交汇，强调了关键生物标志物和新兴治疗策略。虽然几项评估TGF-β拮抗剂、小分子和基于细胞的疗法的临床试验显示出很大的前景，但将它们成功转化为有效、靶向治疗仍面临挑战。尽管如此，持续探索TGF-β在纤维化和衰老中的多方面作用为开发针对PF和其他慢性纤维化疾病的创新疗法带来了希望。
