Regulatory Role Of Otud6a/Prdx1 Axis In Oral Ulcers

Oral ulcer, is a frequent oral inflammatory lesion accompanied by severe pain yet has limited effective treatments. Deubiquitinating enzymes (DUBs) play crucial roles in multiple diseases, as they remove ubiquitin molecules from substrate proteins. Ovarian tumor deubiquitinase 6A (OTUD6A), a specific DUB, regulates cell proliferation and immunomodulatory functions and is involved in various diseases. However, the role of OTUD6A in oral ulcer remains largely unknown. For in vivo study, oral ulcers were induced on murine tongues using acetic acid. Wild-type or Otud6a-/- mice were used for these experiments. Human oral epithelial cells (HOECs) treated with H2O2 were used to elucidate the molecular mechanisms. Additionally, a hydrogel was developed for the delivery of OTUD6A protein to acid-induced oral ulcers on mouse tongues to further assess its therapeutic potential. In vivo and vitro data demonstrated that OTUD6A deficiency aggravated the severity of acid-induced ulcers and inhibited the cell viability of HOECs. Mechanistically, OTUD6A preserved the stability of peroxiredoxin 1 (PRDX1) by cleaving its K48-linked polyubiquitin chains, which subsequently mitigated mitochondrial oxidative stress and enhanced PRDX1-related mitophagy, ultimately leading to the alleviation of oral ulcer. Consistent with these findings, the hydrogel delivering OTUD6A protein attenuated the development of oral ulcer. OTUD6A ameliorated oral ulcer by alleviating mitochondrial dysfunction through the promotion of PRDX1. These findings suggested that OTUD6A could be a promising target for the treatment of oral ulcer.