Researchers from Sun Yat-sen University in China have identified a potential new target for therapies aimed at treating periodontitis that is worsened by smoking. Their study, led by Professor Chuanjiang Zhao, used high-resolution spatial transcriptomics to analyze differences in gene expression between smokers and non-smokers with periodontitis.
Periodontitis is a chronic inflammatory disease affecting the gums, leading to tissue and bone damage around the teeth. It has been established that tobacco smokers are more likely to develop periodontitis, experience faster disease progression, more severe symptoms, and respond less effectively to treatment compared to non-smokers. However, the specific cellular mechanisms behind these differences were not well understood due to previous technological limitations.
The research team employed Visium HD single-cell spatial transcriptomics to map molecular pathways activated in gum tissues of both smokers and non-smokers with periodontitis. Their findings were published in Volume 17 of the International Journal of Oral Science on August 1, 2025.
"Understanding the complex cellular interactions that contribute to disease progression in smoking-associated periodontitis is important," said Prof. Zhao. He continued, "By employing the Visium HD platform, we aimed to map the spatial distribution of different cell types within healthy and diseased periodontal tissues and identify smoking-induced changes in gene expression patterns across various cell populations."
The researchers first investigated how exposure to bacterial lipopolysaccharide (LPS) combined with nicotine affected epithelial cells. They found that this combination caused greater changes in genes related to epithelial structure and inflammation than LPS alone, indicating that smoking may weaken gum barriers and increase susceptibility to inflammation.
When comparing tissue samples from healthy gums, non-smokers with periodontitis, and smokers with periodontitis, they observed notable differences in fibroblasts—the cells responsible for maintaining gum structure. Prof. Zhao explained: "Our results revealed that individuals in the smoking group, as opposed to healthy controls, presented upregulated expression of genes linked to aging, intrinsic apoptotic signaling, and mitotic processes." Fibroblasts from smokers also showed increased expression of genes related to inflammation and immune cell recruitment.
Spatial analysis further revealed that endothelial cells and macrophages were closely positioned only in tissues from smokers with periodontitis. This proximity enabled stronger inflammatory interactions. These tissues also contained a higher proportion of pro-inflammatory macrophages associated with tissue destruction.
A key finding was the role of C-X-C motif chemokine 12 (CXCL12), which is secreted by endothelial cells in gum tissue. The presence of CXCL12 prompted macrophages to become pro-inflammatory; when CXCL12 secretion was suppressed, macrophages became anti-inflammatory instead. Experiments on mice confirmed that reducing CXCL12 lowered inflammation and bone damage caused by nicotine-aggravated periodontitis.
"Targeting CXCL12 shows promise in mitigating inflammation and bone resorption in individuals with smoking-induced periodontitis," said Prof. Zhao about future therapeutic strategies. He added: "Future research should investigate local delivery systems, like nanoparticles or liposomes, to reduce systemic side effects and improve treatment precision."
