# Tobacco-derived particulates and the periodontal axis: Distinct cytotoxic and stress-related mechanisms in human gingival fibroblasts

## TL;DR

This study compares the harmful effects of cigarette and heated tobacco products on gum cells, finding that both cause damage but cigarettes are worse.

## Contribution

The study reveals distinct cytotoxic and stress-related mechanisms of tobacco-derived particulates in human gingival fibroblasts.

## Key findings

- TPM-c caused more cytotoxicity, necrosis, and impaired wound healing than TPM-h.
- TPM-c triggered VEGF-A upregulation, while TPM-h reduced autophagic response.
- Both TPMs elevated IL-6 release, indicating pro-inflammatory effects.

## Abstract

Tobacco products vary widely in their chemical composition and potential harm, yet their impact on oral tissue remains insufficiently characterized. 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 A/1 B-light chain 3-phosphatidyl ethanolamine conjugate/LC3-II (LC3β) 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.

The online version contains supplementary material available at 10.1038/s41598-026-35317-8.