Discovery of a novel benzoselenophene derivative as a potential therapeutic agent for pulmonary fibrosis.

Pulmonary fibrosis is a progressive and fatal disorder with high mortality, and current therapies offer modest efficacy. Single-target interventions are insufficient to address the complex pathological network involving oxidative stress, inflammation, and cascaded fibrosis progression. Herein, a multi-stage cascade screening platform was established for integrating cytotoxicity, anti-inflammatory, antioxidant, and antifibrotic assessments. Systematic structure-activity relationship optimization led to the discovery of a novel benzoselenophene derivative, CX-Se13. It simultaneously regulates Keap1/Nrf2/HO-1/NQO1, NF-κB p65, TGF-β/Smads and YAP/TAZ-TEAD pathways, exerting integrated anti-inflammatory, antioxidant, and antifibrotic effects. In vitro and in vivo evaluations revealed that CX-Se13 suppresses the pathological progression of pulmonary fibrosis, reduces collagen deposition and pro-inflammatory cytokine levels, and exhibits potent protective effects in a bleomycin-induced mouse model of pulmonary fibrosis. CX-Se13 represents a novel, pleiotropic lead compound with high developmental potential, providing a new molecular entity and research paradigm for the development of antifibrotic therapies for pulmonary fibrosis.