Fosinopril mediates antitumor efficacy by inducing GSDME-dependent pyroptosis in NSCLC.

Repurposing existing drugs offers a promising approach to cancer therapy. Fosinopril, an angiotensin converting enzyme inhibitor (ACEI) approved for hypertension, has demonstrated antitumor effects in hepatocellular carcinoma. However, its activity in non-small cell lung cancer (NSCLC) remains poorly understood. Here, we explore the potential anti-NSCLC effects of fosinopril in vitro and in vivo and its action mechanisms. The antiproliferative effects of fosinopril on NSCLC cells were assessed through the A549 and H1299 cell lines. Network pharmacology and proteomics were utilized to predict fosinopril's molecular mechanisms in NSCLC. A subcutaneous xenograft model in nude mice was established to evaluate the in vivo anticancer effects and mechanisms of fosinopril. Fosinopril significantly inhibited the proliferation and colony formation of NSCLC cells. Additionally, fosinopril induced pyroptosis in NSCLC cells, evidenced by GSDME cleavage and increased LDH release. Mechanistically, fosinopril increased ROS levels, which activated Bax and downregulated mitochondrial membrane potential (MMP), resulting in Caspase-9 and Caspase-3 cleavage. Moreover, fosinopril suppressed tumor growth in a subcutaneous xenograft model and activated pyroptosis-related proteins. This study provides the first evidence that fosinopril inhibits NSCLC via GSDME-dependent pyroptosis, triggered by ROS-induced mitochondrial dysfunction and caspase activation. Further investigation into the detailed mechanisms of fosinopril's anti-NSCLC activity is warranted.