Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

Damage-associated molecular patterns (DAMPs) play a critical role in dendritic cells (DCs) ability to trigger a specific and efficient adaptive immune response for different physiological and pathological scenarios. We have previously identified constitutive DAMPs (HMGB1 and Calreticulin) as well as new putative inducible DAMPs such as Haptoglobin (HP), from a therapeutically used heat shock-conditioned melanoma cell lysate (called TRIMEL). Remarkably, HP was shown to be the most abundant protein in the proteomic profile of heat shock-conditioned TRIMEL samples. However, its relative contribution to the observed DCs phenotype has not been fully elucidated. Human DCs were generated from monocytes isolated from PBMC of melanoma patients and healthy donors. DC lineage was induced with rhIL-4 and rhGM-CSF. After additional stimulation with HP, the proteome of these HP-stimulated cells was characterized. In addition, DCs were phenotypically characterized by flow cytometry for canonical maturation markers and cytokine production. Finally, in vitro transmigration capacity was assessed using Transwell plates. Our results showed that the stimulation with HP was associated with the presence of exclusive and higher relative abundance of specific immune-; energy production-; lipid biosynthesis-; and DAMPs-related proteins. Importantly, HP stimulation enhanced the expression of specific DC maturation markers and pro-inflammatory and Th1-associated cytokines, and an in vitro transmigration of primary human DCs. Taken together, these data suggest that HP can be considered as a new inducible DAMP with an important role in in vitro DC activation for cancer immunotherapy.

Despite the understanding of the coronavirus disease-19 (COVID-19), the role of salivary extracellular vesicles (sEVs) in COVID-19 remains unclear. Exploring the proteomic cargo of sEVs could prove valuable for diagnostic and prognostic purposes in assessing COVID-19. The proteomic cargo of sEVs from COVID-19(+) subjects and their healthy close contacts (HCC) was explored. sEVs were isolated by ultracentrifugation from unstimulated saliva samples, and subsequently characterized through nanoparticle tracking, transmission electron microscopy, and Western blot analyses. The proteomic cargo of sEVs was processed by LC-MS/MS. sEVs were morphologically compatible with EVs, with the presence of Syntenin-1 and CD81 EV markers. The sEV pellet showed 1417 proteins: 1288 in COVID-19(+) cases and 1382 in HCC. In total, 124 proteins were differentially expressed in sEVs from COVID-19(+) subjects. “Coronavirus-disease response”, “complement and coagulation cascades”, and “PMN extracellular trap formation” were the most enriched KEGG pathways in COVID-19(+) cases. The most represented biological processes were “Hemoglobin and haptoglobin binding” and “oxygen carrier activity”, and the best-denoted molecular functions were “regulated exocytosis and secretion” and “leucocyte and PMN mediated immunity”. sEV proteomic cargo in COVID-19(+) suggests activity related to immune response processes, oxygen transport, and antioxidant mechanisms. In contrast, in HCC, sEV signature profiles are mainly associated with epithelial homeostasis.

Regulated cell death (RCD) and survival pathways have emerged as critical factors in periodontal tissue breakdown. However, their precise roles and interactions remain poorly understood. This systematic review aimed to synthesize current evidence regarding the involvement of RCD and survival mechanisms in the progression of periodontitis. A systematic literature search was conducted in PubMed/MEDLINE, Web of Science and Scopus, complemented by manual searching in Google Scholar, following PRISMA guidelines. After removing duplicates, 549 studies underwent title and abstract screening. Of these, 56 articles were selected for full-text review and 18 studies met the eligibility criteria and were included in the final synthesis. Ferroptosis, pyroptosis and necroptosis were consistently associated with inflammatory exacerbation, alveolar bone loss and disease progression. In contrast, autophagy and apoptosis exhibited dual roles—protective or destructive—depending on cell types, disease stage and experimental conditions. Most studies utilized ligature-induced periodontitis animal models. Several studies also demonstrated the therapeutic potential of modulating specific RCD pathways to control inflammation and promote periodontal tissue regeneration, highlighting possible translational strategies for host-modulation therapy of periodontitis. This systematic review consolidates the pivotal role of RCD in the progression of periodontitis. Targeting RCD pathways may represent novel therapeutic strategies to reduce periodontal inflammation and tissue destruction.

Introduction: Guided bone regeneration (GBR) is a key approach for managing alveolar ridge defects. Although titanium meshes are widely used for non-resorbable space maintenance, their limitations have prompted interest in alternative materials. Polyetheretherketone (PEEK), a high-performance thermoplastic, has emerged as a potential barrier due to its mechanical strength, radiolucency, and compatibility with digital workflows. Objective: To map the current evidence on the use of PEEK barriers in GBR, focusing on biological performance, mechanical properties, and clinical outcomes in animal and human studies. Methods: A scoping review was conducted following PRISMA-ScR guidelines. Eligible studies included in vivo animal models or clinical trials involving PEEK barriers for alveolar bone regeneration. Data on study design, defect type, barrier characteristics, surgical protocol, outcomes, and complications were extracted. Results: Five studies met the inclusion criteria: two animal models and three clinical trials. All reported successful space maintenance and bone gain with PEEK barriers, with outcomes comparable to titanium meshes. Customization through CAD/CAM or 3D printing was common. Complications such as soft tissue dehiscence and exposure occurred but generally did not affect regeneration. Evidence was limited by small sample sizes, short follow-up, and single-center designs. Conclusions: PEEK barriers show promise as customizable alternatives to traditional GBR membranes. However, current evidence is limited and geographically concentrated. Future multicenter studies with long-term follow-up and standardized outcome measures are needed to validate the clinical potential of PEEK in bone regeneration.