Busan National University Research Team Reveals Mechanism of Salivary Gland Damage Caused by Hormonal Imbalance

Professor Hyung-Sik Kim of the Dental School and Professor Byung-Joo Lee of the Medical School Joint Research Team Publish Paper

Identification of Causes of Salivary Gland Damage After Pneumonectomy, Elucidation of Cell Death Mechanism in Saliva-Producing Cells Induced by TGF-β2

The cause of severe dry mouth and xerostomia after menopause has been identified.

On the 4th, Busan National University (President Choi Jae-won) announced that a research team led by Professor Kim Hyung-sik of the School of Dentistry and Professor Lee Byung-joo of the Department of Otorhinolaryngology at the College of Medicine revealed the cause of xerostomia after menopause and suggested new therapeutic possibilities to control it.

The research team discovered that after menopause, the increase of TGF-β2 (Transforming Growth Factor-beta 2) in salivary gland tissue disrupts the intracellular balance of iron ions, leading to the death of acinar cells responsible for saliva production through ferroptosis, an iron-dependent cell death mechanism.

Ferroptosis using salivary gland organoids.

Ferroptosis refers to an iron-dependent form of cell death, and acinar cells are the cells within the salivary glands responsible for producing saliva.

'Xerostomia' is a disease caused by decreased function of the salivary glands and is reported to have a particularly high prevalence among postmenopausal women. The decline in salivary gland function causes symptoms such as dry mouth, swallowing and taste disorders, halitosis, oral inflammation, and dental caries, significantly reducing patients' quality of life. However, treatments to date have focused only on temporary symptom relief.

Accordingly, the research team aimed to propose fundamental prevention and treatment technologies for xerostomia by identifying iron-dependent cell death as a major cause of salivary gland damage and attempting new approaches to control it.

The team found that in an ovariectomized mouse model, salivary gland function was impaired, and at this time, TGF-β2 signaling and ferroptosis, an iron-dependent cell death, were activated in the salivary gland tissue.

To specify the activation mechanism discovered in the animal model, the researchers produced salivary gland organoids from mice and humans and demonstrated that TGF-β2 disrupts the intracellular iron ion storage and recycling mechanisms in salivary gland epithelial cells, inducing cell death via ferroptosis.

Organoids are organ-like structures produced by inducing self-organization of stem cells cultured in three dimensions.

Finally, through animal experiments, the research team confirmed that the ferroptosis inhibitor liproxstatin-1 could be effective in preventing xerostomia. Specifically, administration of the ferroptosis inhibitor preserved both the saliva secretion volume and the distribution area of acinar cells, which decrease after ovariectomy. Additionally, analysis of patient tissues confirmed that the newly identified mechanism causes damage to patients' salivary glands.

This study elucidated the fundamental cause of xerostomia after menopause and suggested the possibility of effective prevention or treatment. In particular, by inhibiting iron-dependent cell death or the signals inducing it, salivary gland function can be restored, presenting a new approach to treating xerostomia. Since other exocrine glands, such as the lacrimal glands, have very similar structures and functions to salivary glands, these findings are expected to be extended and applied to diseases caused by dysfunction of other exocrine glands.

Professor Kim Hyung-sik of Busan National University stated, "Through this study on menopausal xerostomia, we have begun to see clues to solving senile xerostomia, and we plan to verify through follow-up research whether the discovered mechanism is commonly observed in general senile xerostomia."

Mechanism of salivary gland acinar cell apoptosis due to estrogen deficiency.

This study was published on October 31 in the international journal Advanced Science under the title "TGFβ2-Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions."

This research was supported by the Ministry of Science and ICT and the National Research Foundation of Korea through the Bio-Medical Technology Development Project (Development of Treatment Technology for Intractable Diseases Based on Stem Cell ATLAS). Doctoral student Oh Soo-jung and Dr. Shin Ye-young from the School of Dentistry were first authors, and Professor Lee Byung-joo of the College of Medicine, Dr. Seo Yoo-jin of the School of Dentistry, and Professor Kim Hyung-sik served as corresponding authors.

This content was produced with the assistance of AI translation services.