Single-cell and Spatial Transcriptomic Profiling Reveal that LAPTM5-mediated Ferroptosis in Macrophages Induces...

Periodontitis represents a persistent inflammatory condition marked by gradual damage to the gingival connective tissues and alveolar bone. Programmed cell death (PCD) is essential for preserving immune balance and includes various forms such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Nevertheless, the principal PCD pathway that contributes periodontal inflammation has not been clearly identified. In this work, we integrated multiple publicly available single-cell RNA sequencing datasets and applied diverse gene set scoring approaches to systematically characterize the dynamic expression of PCD-associated genes in periodontitis-affected tissues. Ferroptosis emerged as one of the important PCD pathways, mainly occurring in macrophages. Cell-cell communication and spatial analyses suggested that ferroptotic macrophages were located adjacent to fibroblast-enriched regions and may interact with fibroblasts through Galectin and OSM signaling pathways. Functionally, ferroptotic macrophages suppressed fibroblast proliferation and migration while amplifying their pro-inflammatory response, underscoring their pivotal role in sustaining chronic inflammation. Furthermore, machine-learning analyses identified LAPTM5 as one of the ferroptosis-associated hub genes in macrophages. Knockdown of LAPTM5 in macrophages suppressed ferroptosis and subsequently attenuated fibroblast inflammatory responses. Collectively, our study highlights ferroptosis as one of the key pathogenic mechanisms in periodontitis and identifies LAPTM5-driven macrophage ferroptosis as a key driver of fibroblast dysfunction and chronic inflammation, providing potential therapeutic insights for restoring periodontal immune balance.