Decoding Pyroptosis in Pulmonary Fibrosis: Molecular Mechanisms and Therapeutic Horizons
Shuqi Zheng, Chunlei Hua, Wanze Feng, Zengxia Liu, Haibin Wang, Lixin Zhao, Tuya Xilin, Boyang Yu, Minhui LiAbstract:
Background: Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by the depletion of alveolar epithelial cells (AECs) and the pathological accumulation of extracellular matrix (ECM). Despite its high mortality rate, the molecular drivers of PF progression remain partially understood. Recent evidence suggests that pyroptosis, a pro-inflammatory programmed cell death, plays a pivotal role in orchestrating the inflammatory cascade and fibrotic remodeling in the lung. Methods: This study employed bibliometric and visual analysis via CiteSpace 6.2.4 to systematically map the research landscape of pyroptosis in PF using the Web of Science Core Collection (2010-2025). Based on the identified hotspots, a comprehensive review of the molecular activation pathways and cell-specific mechanisms was conducted. Results: Bibliometric analysis (Modularity Q=0.5381, Silhouette S=0.8236) revealed a significant shift in research focus from basic pathological descriptions (2010-2015) to detailed pyroptotic mechanisms (2015- 2020), with immune checkpoint inhibitors emerging as the latest frontier since 2020. Mechanistically, we propose an "Initiation-Amplification-Persistence" model: AEC pyroptosis initiates epithelial barrier disruption; macrophage pyroptosis amplifies the inflammatory storm and polarizes the immune microenvironment; and fibroblast activation sustains ECM deposition. Furthermore, we summarized potential therapeutic interventions, including small molecule synthetic compounds (Nintedanib, Pirfenidone, MCC950, VX-765, etc.), natural products (Lycorine, Tanshinone IIA, etc.) and biologically active substances (Canakinumab, Anakinra) that exhibit multi-pathway synergistic effects. Conclusion: Targeting the pyroptosis signaling axis offers a promising strategy for reversing PF progression. Future research should prioritize the identification of pyroptosis- related biomarkers and the development of lung-targeted delivery systems to facilitate clinical translation and precision intervention.