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This study comparatively investigated the cytotoxic, oxidative, and inflammatory responses, along with apoptotic\/necrotic cell death, autophagosome formation, and tissue remodeling capacity, in human gingival fibroblasts (hGFs) exposed to total particulate matter (TPM) derived from a conventional cigarette (TPM-c) and a heated tobacco product (TPM-h). TPMs were chemically characterized by inductively coupled plasma mass spectrometry (ICP-MS) for heavy metal content. TPM-c induced notable cytotoxicity, necrosis, and impaired wound healing compared to TPM-h, although both products compromised hGF viability and function. In addition, higher levels of Cadmium (Cd), Lead (Pb), and Zinc (Zn) were detected in TPM-c. Triggered vascular endothelial growth factor-A (VEGF-A) upregulation as a defensive reaction to cellular stress was observed in hGFs via TPM-c, while TPM-h reduced autophagic response via Microtubule-associated protein 1\u00a0A\/1 B-light chain 3-phosphatidyl ethanolamine conjugate\/LC3-II (LC3\u03b2) expression. Both TPMs elevated interleukin-6 (IL-6) release, notably at intermediate and high doses. In summary, TPM-c demonstrated a greater capacity than TPM-h to induce cytotoxicity, oxidative and inflammatory damage, and disrupted tissue remodeling. Nonetheless, TPM-h was not devoid of toxicity, eliciting pro-inflammatory\/ angiogenic responses concentration-dependently. These findings highlight the necessity of further investigation into the long-term effects of emerging tobacco products on periodontal disease progression and development.<\/jats:p>","DOI":"10.1038\/s41598-026-35317-8","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T15:36:55Z","timestamp":1771947415000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tobacco-derived particulates and the periodontal axis: Distinct cytotoxic and stress-related mechanisms in human gingival fibroblasts"],"prefix":"10.1038","volume":"16","author":[{"given":"K.","family":"Kolci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Yildirim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Azevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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