Harnessing TP73‑targeted nintedanib: A novel strategy to halt triple‑negative breast cancer via p53‑PPARα/PI3K‑Akt pathway suppression

Triple‑negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, leading to poor clinical outcomes and the need for novel therapeutic approaches. Nintedanib, a United States Food and Drug Administration‑approved multi‑kinase inhibitor with anti‑fibrotic and anti‑angiogenic properties, has shown promise in cancer treatment. However, its precise molecular effects on TNBC have not yet been fully elucidated. Therefore, the present study aimed to investigate the therapeutic potential of nintedanib in TNBC using in vitro and in vivo models, specifically focusing on its regulatory effects on key oncogenic pathways. The present study utilized TNBC cell lines (MDA‑MB‑231 and 4T1) and BALB/c mice to evaluate the antitumor efficacy of nintedanib. Cell viability and clonogenic capacity were assessed using Cell Counting Kit‑8 and colony formation assays. Subsequently, apoptosis induction and cell cycle progression were determined by flow cytometry, and cell migration and invasion were analyzed through scratch and Transwell assays. To identify underlying mechanisms, potential molecular targets were identified via bioinformatics and network pharmacology, and were validated through western blotting, immunofluorescence and immunohistochemistry. Finally, an orthotopic TNBC mouse model was established and monitored in real time by multimodal ultrasound imaging. The results revealed that nintedanib significantly inhibited TNBC cell proliferation and suppressed stem cell‑like properties. Furthermore, it induced cell cycle arrest at the G₂/M phase and promoted apoptosis. Mechanistic analysis revealed that nintedanib activated tumor protein p73 (TP73), leading to the disruption of the p53‑peroxisome proliferator‑activated receptor α (PPARα)/PI3K‑Akt signaling axis. Additionally, it downregulated epithelial‑mesenchymal transition (EMT) markers, including Snail and zinc finger E‑box‑binding homeobox protein 1, thereby mitigating tumor invasiveness. In vivo, nintedanib treatment effectively reduced tumor growth, angiogenesis and stiffness, indicating its potential as a viable therapeutic agent for TNBC. In conclusion, nintedanib exerts potent anti‑TNBC effects by modulating TP73, disrupting oncogenic signaling via the p53‑PPARα/PI3K‑Akt axis, and attenuating EMT‑associated transcription factors. These findings highlight its potential as a promising targeted therapy for TNBC, warranting further clinical exploration.