Abstract
Abstract One common plasticizer is di(2-ethylhexyl) phthalate (DEHP). We use it a lot in our daily lives, and prolonged exposure to it can be harmful to living things. One form of selective autophagy that can break down damaged lysosomes is called lysophagy. Conversely, excessive occurrence of lysophagy can in turn cause lysosomal damage. Here, we show that DEHP stimulates the transient receptor potential mucoLipin 1-transcription factor EB (TRPML1-TFEB) pathway, drives excessive lysophagy, resulting in lysosomal dysfunction and kidney injury in mice. One carotenoid with strong antioxidant qualities is lycopene (LYC). It is frequently employed to offset the effects of DEHP. Interestingly, our results showed that LYC can reduce kidney damage caused by DEHP in mice. Inhibiting the TRPML1-TFEB pathway's activation and reducing lysophagy are two of the mechanisms of action. In summary, LYC significantly alleviates DEHP-induced injury in mouse renal tubular epithelial cells by inhibiting TRPML1-TFEB pathway-mediated lysophagy. LYC successfully reduced the damage caused by mono(2-ethylhexyl) phthalate in human renal proximal tubular epithelial cells, confirming this effect in vitro. This study establishes a critical link between LYC treatment and lysophagy as well as lysosomal dysfunction in DEHP-induced mouse renal tubular epithelial cells. This study offers novel mechanistic perspectives on DEHP-induced nephrotoxicity and the renal protection conferred by LYC. Graphical Abstract