Vitamin A Deficiency Disrupts Retinoic Acid Metabolic Homeostasis to Drive Inflammatory and Regenerative Imbalance in Periodontitis

Objectives Vitamin A deficiency (VAD) impairs immune function and tissue homeostasis, yet its role in periodontitis remains incompletely understood. This study aimed to investigate whether impaired vitamin A/retinoic acid (VA/RA) metabolism contributes to the initiation and progression of periodontitis and to elucidate the underlying molecular mechanisms. Methods We conducted a narrative synthesis of three published analyses based on U.S. National Health and Nutrition Examination Survey (NHANES) data. A ligature-induced periodontitis model was established in vitamin A-deficient (VAD) mice, and the animals were divided into control, periodontitis (PD), PD + VAD, PD + RA, and PD + VAD + RA groups. Periodontal tissue destruction, macrophage polarization, and NF-κB pathway activity were assessed by micro‑CT, histopathology, immunofluorescence, qRT‑PCR, Western blot, and ELISA. In vitro, THP‑1-derived macrophages, human periodontal ligament stem cells (hPDLSCs), and an osteoclast differentiation model were used, together with transcriptome sequencing and the NF‑κB inhibitor BAY 11‑7082, to validate the signalling pathway. Results Published NHANES analyses consistently reported an inverse association between vitamin A or retinol intake and periodontitis severity or risk. VAD aggravated periodontal inflammation and alveolar bone loss in mice, which were partially reversed by RA gavage. VAD decreased the expression of RBP4 and RARB in periodontal tissues, enhanced activation of MyD88/TRIF/NF-κB signalling, promoted macrophage M1 polarization (significant upregulation of CD86, IL‑1β, and TNF‑α), and suppressed M2 polarization (marked downregulation of CD206 and IL‑10). Transcriptome sequencing revealed significant enrichment of the NF-κB signalling pathway, and both RA (1 μM) and BAY 11‑7082 inhibited NF-κB pathway activity. In vitro experiments confirmed that VAD exacerbated Porphyromonas gingivalis‑derived lipopolysaccharide induced macrophage M1 polarization and osteoclast differentiation, and conditioned medium from macrophages under VAD conditions inhibited the osteogenic differentiation of hPDLSCs (attenuated ALP and ARS staining, downregulation of osteogenic genes). Conclusions Impaired VA/RA metabolism was associated with increased MyD88/TRIF/NF-κB pathway activity, a shift toward a pro-inflammatory macrophage phenotype, reduced osteogenic capacity, and enhanced osteoclast differentiation, thereby potentially contributing to periodontitis progression. RA supplementation partially attenuated these alterations in the experimental models, supporting further investigation of RA as a potential adjunctive strategy for periodontitis.