TIMP3 deficiency accelerates UVB-induced HaCaT cell senescence by regulating ferroptosis.

Abstract

Prolonged exposure to ultraviolet B (UVB) light leads to the accumulation of reactive oxygen species (ROS), a key contributor to skin aging. Previous studies have demonstrated that UVB exposure results in a deficiency in the expression of TIMP3 in keratinocytes. The objective of this study was to investigate the specific role of TIMP3 in keratinocytes. UVB-treated HaCaT cells were utilized to establish a cellular photoaging model. We found that UVB significantly increased levels of ROS, promoted senescence and ferroptosis, and inhibited the expression of TIMP3 in HaCaT. This inhibition was notably alleviated by Fer-1, a ferroptosis inhibitor. In addition, the knockdown of TIMP3 in HaCaT enhanced senescence by inducing the ferroptosis. Mechanistically, UVB exposure also led to a decrease in the expression of KLF4, a transcription factor that regulated TIMP3 expression. Futhermore, UVB-induced reduced expression of KLF4 and TIMP3 in vivo. Our results suggest that deletion of the KLF4/TIMP3 axis promotes HaCaT cell senescence by facilitating the progression of ferroptosis. TIMP3 may serve as an effective therapeutic target for preventing skin photoaging.