# Sunitinib Impairs Oral Mucosal Healing Through Endoplasmic Reticulum Stress-Mediated Keratinocyte Dysfunction

## TL;DR

This study shows that the drug sunitinib impairs oral mucosal healing by causing stress in cells' endoplasmic reticulum, which can be reversed by targeting this stress.

## Contribution

The study identifies endoplasmic reticulum stress as a novel mechanism by which sunitinib impairs mucosal healing and suggests targeting this pathway as a therapeutic strategy.

## Key findings

- Sunitinib causes endoplasmic reticulum stress in keratinocytes, impairing mucosal healing.
- Pharmacological inhibition of ER stress restores keratinocyte function and mucosal healing.
- Sunitinib activates the GRP78/PERK/ATF4/CHOP pathway, leading to cell dysfunction and apoptosis.

## Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event triggered by antiresorptive and/or anti-angiogenic agents, characterized by bone destruction, sequestrum formation, and refractory mucosal defects. Effective mucosal healing can be a critical factor for MRONJ prevention and treatment. While endoplasmic reticulum stress (ER stress) has been implicated in tissue repair, its role in MRONJ-associated mucosal healing impairment remains undefined. This study investigated the effects of the anti-angiogenic drug sunitinib on oral mucosal healing and its underlying mechanisms. A mouse model of palatal mucosal defects was established, RNA-seq, transmission electron microscopy, and morphological analyses were used to assess how sunitinib affects ER function during mucosal repair. Using human oral keratinocytes (HOKs), we further elucidated the subcellular mechanisms through which sunitinib influences cell proliferation, migration, cell cycle progression, tight junctions, and apoptosis via techniques such as qPCR, Western blotting, immunofluorescence, and flow cytometry. Our findings demonstrated that sunitinib might induce significant alterations in the morphology of the ER and mitochondria. Both in vivo and in vitro experiments revealed that sunitinib persistently activates the GRP78 (BIP)/PERK/ATF4/CHOP axis in HOKs. This sustained ER stress can inhibit keratinocytes migration and proliferation, disrupt tight junctions, and trigger the intrinsic mitochondrial apoptotic pathway, ultimately leading to impaired oral mucosal healing and barrier dysfunction. Critically, pharmacological inhibition of ER stress was shown to restore keratinocytes’ function and promote effective mucosal healing. These results indicated that targeting sunitinib-induced persistent ER stress might represent a promising therapeutic strategy to prevent and treat oral mucosal toxicity associated with this drug.