Silica Nanoparticles Trigger Chaperone HSPB8‐Assisted Selective Autophagy via TFEB Activation in Hepatocytes

Abstract Silica nanoparticles (SiNPs) are one of the most common inorganic nanomaterials. Autophagy is the predominant biological response to nanoparticles and transcription factor EB (TFEB) is a master regulator of the autophagy–lysosome pathway. Previous studies show that SiNPs induce autophagosome accumulation, yet the precise underlying mechanisms remain uncertain. The present study investigates the role of TFEB during SiNP‐induced autophagy. SiNP‐induced TFEB nuclear translocation is verified using immunofluorescence and western blot assay. The regulation of TFEB is proved to be via EIF2AK3 pathway. A TFEB knockout (KO) cell line is constructed to validate the TFEB involvement in SiNP‐induced autophagy. The transcriptomes of wild‐type and TFEB KO cells are compared using RNA‐sequencing to identify genes of the TFEB‐mediated autophagy and lysosome pathways affected by SiNPs. Based on these data and the Human Autophagy Database, four candidate autophagic genes are identified, including HSPB8 , ATG4D , CTSB and CTSD . Specifically, that the chaperone HSPB8 is upregulated through SiNP‐mediated TFEB activation and forms a chaperone‐assisted selective autophagy (CASA) complex with BAG3 and HSC70, triggering HSPB8‐assisted selective autophagy, is found. Thus, this study characterizes a novel mechanism underlying SiNP‐induced autophagy that helps pave the way for further research on the toxicity and risk assessment of SiNPs.