High‐Fat Diet Reprograms the Periapical Immune Landscape in a Mouse Model of Apical Periodontitis: A Spatial Transcriptomics Study

INTRODUCTION: Apical periodontitis (AP) is an inflammatory disease of the periapical tissues driven by host responses to endodontic infection, and systemic metabolic disturbances, such as high-fat diet (HFD)-induced dysmetabolism, may exacerbate tissue destruction. This study aimed to determine how chronic HFD exposure alters periapical myeloid cell states and lesion characteristics in a mouse model of AP using spatially resolved transcriptomics. METHODS: Male C57BL/6 mice (n = 20; 6-8 weeks, specific pathogen-free) were randomly assigned to normal chow (NC) or 60% HFD for 18 weeks, with AP induced by pulp exposure in first molars after 14 weeks. Body weight and fasting blood glucose were monitored longitudinally; apical lesion volume was quantified by high-resolution micro-CT and histology at 28 days post-induction; and periapical tissues from AP and contralateral control sites underwent 10× Genomics Xenium in situ spatial transcriptomics focused on neutrophils and macrophages. RESULTS: Compared with NC, HFD mice developed greater body weight gain, higher fasting glucose (approximately 9-11 mM vs. 6-8 mM) and significantly larger apical lesion volumes by micro-CT (p ≤ 0.05), confirming an obese, dysmetabolic background with exacerbated AP-associated bone loss. Spatial transcriptomics revealed that in non-lesion tissues, HFD-conditioned neutrophils and macrophages were biased toward lipid-handling, stress-adaptive and inflammasome-associated programs, whereas NC maintained antimicrobial and oxidative effector signatures. Within AP lesions, HFD was associated with foam cell-like macrophage phenotypes and neutrophils with reduced degranulation and bactericidal gene expression, while NC lesions preserved antigen presentation, neutrophil effector pathways and structured tissue-remodelling responses. CONCLUSIONS: Chronic high-fat feeding reprograms periapical innate immunity from antimicrobial defence toward lipid-driven fibro-inflammatory states, thereby amplifying apical bone loss in AP. These findings highlight spatial transcriptomics as a powerful approach to map immunometabolic circuits in endodontic disease and suggest potential targets for managing AP in metabolically compromised patients.