Design, synthesis, and biological evaluation of a dual-action agent targeting bromodomain and extraterminal domain and HS release for the treatment of hepatic and pulmonary injury.

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.