Zhu Yanghui, Wang Lian, Pan Zhaoping, Liu Mingxia, Wu Fengbo, Wen Xiang, He Gu
Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2025 Oct 15;296:117887. doi: 10.1016/j.ejmech.2025.117887. Epub 2025 Jun 18.
Organ injury represents one of the leading causes of mortality worldwide, severely impacting patients' quality of life while imposing substantial economic and psychological burdens. Both hepatic and pulmonary injuries can trigger pro-inflammatory cascades, subsequently promoting fibrosis, cirrhosis, and ultimately organ failure. Organ fibrosis is characterized by excessive extracellular matrix deposition and is strongly associated with increased morbidity and mortality. In this study, we designed and synthesized a series of novel compounds based on JQ-1 and anethole trithione (ATT) that simultaneously release hydrogen sulfide (HS) and inhibit bromodomain and extraterminal domain proteins (BET), with the aim of attenuating liver and lung injuries. Among these compounds, 11r demonstrated exceptional efficacy in HS release and significantly suppressed the CCl-induced upregulation of fibrosis markers (α-SMA and fibronectin), c-Myc, and CDC25B, while also reducing cellular apoptosis in LO2 hepatocytes. In a CCl-induced murine liver fibrosis model, daily oral administration of 11r (30 mg/kg) for three consecutive days significantly improved hepatic function, restored damaged liver architecture, and reduced collagen deposition, exhibiting superior therapeutic efficacy compared to JQ-1 or ATT monotherapy. Furthermore, 11r extended the survival duration of CCl-treated mice and mitigated systemic damage including spleen and lungs. Notably, 11r also enhanced pulmonary function and diminished collagen accumulation in a bleomycin (BLM)-induced murine pulmonary fibrosis model. Our studies demonstrate that compound 11r represents a promising therapeutic candidate for the treatment of hepatic and pulmonary fibrosis. This study not only highlights the potential synergistic benefits of combining BRD4 inhibition with HS donation for fibrotic disease management but also establishes a foundation for future clinical investigations and mechanistic studies to further elucidate the underlying pharmacological mechanisms.
器官损伤是全球范围内主要的死亡原因之一，严重影响患者的生活质量，同时带来巨大的经济和心理负担。肝脏和肺部损伤均可引发促炎级联反应，进而促进纤维化、肝硬化，最终导致器官衰竭。器官纤维化的特征是细胞外基质过度沉积，与发病率和死亡率的增加密切相关。在本研究中，我们基于JQ-1和茴三硫（ATT）设计并合成了一系列新型化合物，它们能同时释放硫化氢（HS）并抑制溴结构域和额外末端结构域蛋白（BET），旨在减轻肝脏和肺部损伤。在这些化合物中，11r在HS释放方面表现出卓越的功效，并显著抑制了四氯化碳（CCl）诱导的纤维化标志物（α-平滑肌肌动蛋白和纤连蛋白）、c-Myc和细胞周期蛋白依赖性激酶25B（CDC25B）的上调，同时还减少了LO2肝细胞中的细胞凋亡。在CCl诱导的小鼠肝纤维化模型中，连续三天每日口服11r（30 mg/kg）可显著改善肝功能，恢复受损的肝脏结构，并减少胶原蛋白沉积，与JQ-1或ATT单一疗法相比，显示出卓越的治疗效果。此外，11r延长了CCl处理小鼠的存活时间，并减轻了包括脾脏和肺部在内的全身损伤。值得注意的是，在博来霉素（BLM）诱导的小鼠肺纤维化模型中，11r还增强了肺功能并减少了胶原蛋白积累。我们的研究表明，化合物11r是治疗肝纤维化和肺纤维化的有前景的治疗候选物。本研究不仅突出了将BRD4抑制与HS供体相结合用于纤维化疾病管理的潜在协同益处，还为未来的临床研究和机制研究奠定了基础，以进一步阐明潜在的药理机制。
