A Vaginal Secretion-Derived Metabolite Drives HMOX1/Fe2+ Axis-Mediated Ferroptosis in Mucosal Damage of Senile Vaginitis.

AIMS: Senile vaginitis is a common clinical condition with limited treatment options. Estrogen deficiency leads to atrophy of the vaginal walls and thinning of the mucosa. It is noteworthy that although vaginal atrophy is an almost universal consequence of menopause, many postmenopausal women do not develop genitourinary symptoms. These observations collectively indicate that estrogen-independent pathogenic mechanisms are involved. In our preliminary study, through metabolomic screening, we identified three functionally relevant metabolites, namely guggulsterone (GS), umbelliprenin, and inosinic acid. This study seeks to elucidate the pathogenic mechanism of GS in senile vaginitis and to unveil novel therapeutic avenues for this condition.

RESULTS: Cellular and animal experiments confirm that GS elevates intracellular ferrous iron (Fe2+), malondialdehyde, and reactive oxygen species levels in vaginal epithelial cells, thereby inducing ferroptosis and upregulating the expression of inflammatory factors in vaginal tissues. Consequently, these processes compromise vaginal mucosal integrity, thereby exacerbating epithelial atrophy and the progression of inflammation. Treatment with the ferroptosis inhibitor ferrostatin-1 partially reversed the accumulation of Fe2+, lipid peroxides, and cellular oxidative stress. By utilizing a combination of lipidomic mass spectrometry, molecular docking, and surface plasmon resonance, it was collectively demonstrated that GS directly binds to heme oxygenase 1 (HMOX1). Utilizing VK2/E6E7 cell models with lentivirus-mediated HMOX1 knockdown and overexpression, this study demonstrates that GS might contribute to ferroptosis in vaginal epithelial cells by upregulating HMOX1 expression. Notably, treatment with MG132 potentiated the GS-induced upregulation of HMOX1, whereas the autophagy-lysosome inhibitor bafilomycin A1 had no significant effect. These findings suggest that GS may upregulate HMOX1 levels by inhibiting its degradation through the proteasome pathway.

INNOVATION AND CONCLUSION: Collectively, these findings establish GS as a critical regulator of vaginal epithelial cell ferroptosis through HMOX1 targeting, revealing new therapeutic avenues for senile vaginitis. Antioxid. Redox Signal. 45, 618-635.