Upregulation of the TFEB-mediated lysosome function relieves 4-Hydroxynonenal-Induced apoptosis

4-Hydroxynonenal (4-HNE), the most toxic end-product of lipid peroxidation formed during oxidative stress, has been implicated in many diseases including neurodegenerative diseases, metabolic diseases, myocardial diseases, cancer and age-related diseases. 4-HNE can actively react with DNA, proteins and lipids, causing rapid cell death. The accumulation of 4-HNE leads to induction of autophagy, which clears damaged proteins and organelles. However, the underlying mechanism of 4-HNE-regulated autophagy is still not known. Transcriptional factor EB (TFEB) is a master regulator of lysosomal and autophagic functions, which we show here that TFEB is activated by 4-HNE. 4-HNE induces TFEB nuclear translocation and activated TFEB then upregulates the expression of genes required for autophagic and lysosomal biogenesis and function. Reactive oxygen species and Ca²⁺ are required in this process and TFEB activity is required for 4-HNE-mediated lysosomal function. Most importantly, genetic inhibition of TFEB (TFEB-KO) exacerbates 4-HNE-induced cell death, suggesting that TFEB is essential for cellular adaptive response to 4-HNE-induced cell damage. Hence, targeting TFEB to promote autophagic and lysosomal function may represent a promising approach to treat neurodegenerative and metabolic diseases in which 4-HNE accumulation has been implicated.