Avobenzone induces intestinal injury by targeting ATG14 and impairing mitophagy

Avobenzone (Avo) is a widely used ultraviolet filter in sunscreens and facial skincare products. In addition to dermal exposure, chronic oral intake may also occur through daily-use products. However, the potential intestinal toxicity of Avo and its underlying mechanisms remain poorly understood.

We investigated the intestinal effects of Avo using repeated oral exposure mouse models, the Caco-2 intestinal epithelial cell line, human intestinal organoids, proteomic analysis, and mechanistic assays examining autophagy, mitophagy, mitochondrial stress responses, and Wnt/β-catenin signaling.

Administration of Avo (10-40 mg/kg) for two months induced intestinal epithelial injury in mice, as evidenced by reduced crypt number, shortened villi, impaired intestinal epithelial barrier, and decreased intestinal stem cell abundance. Avo also caused mitochondrial dysfunction, oxidative stress, and lipid accumulation. Mechanistically, Avo interacted with ATG14, a key component of the autophagy initiation complex, and promoted CUL3-mediated ubiquitination and proteasomal degradation of ATG14. Loss of ATG14 impaired mitophagy, leading to the accumulation of damaged mitochondria and activation of eIF2α-ATF5-associated mitochondrial unfolded protein response (UPR^mt). This mitochondrial stress suppressed Wnt/β-catenin signaling, reduced maintenance of LGR5-positive intestinal stem cells, and ultimately disrupted epithelial regeneration. Importantly, pharmacological induction of autophagy with rapamycin or inhibition of stress signaling with ISRIB alleviated Avo-induced intestinal injury in mice. Similar effects were observed in human intestinal organoids.

These findings identify a previously unrecognized intestinal toxicity associated with Avo exposure and suggest that disruption of ATG14-dependent mitophagy and mitochondrial quality control is a key mechanism underlying this effect.