Dual mechanism of autophagy gene repression by PHF23 and therapeutic potential of its inhibition in protein aggregation disorders

Autophagy is a conserved self-digestion pathway essential for maintaining cellular homeostasis. While the transcriptional and epigenetic activation of autophagy under nutrient-deprived condition is well studied, the repression mechanisms of autophagy under basal conditions remain poorly understood. Here, we identify plant homeodomain finger protein 23 (PHF23) as an epigenetic repressor of autophagy through a CRISPR interference screen. Importantly, PHF23 inhibits autophagy gene expression via two distinct mechanisms: by recruiting the nucleosome remodeling and deacetylase (NuRD) complex to autophagy gene promoters, and by reducing chromatin accessibility at enhancers through downregulation of AP-1 and C/EBPβ transcription factors. This dual repression requires an intact plant homeodomain (PHD) and is relieved following PHF23 degradation under amino acid starvation or mTOR inhibition. Notably, genetic or pharmacological inhibition of PHF23 induces autophagy and promotes the autophagic clearance of pathological protein aggregates, including Tau and α1-antitrypsin Z (ATZ) variant, highlighting PHF23 as a potential therapeutic target in proteotoxic diseases.