USF2 is a bHLH transcription factor that binds E-box elements (5'-CACGTG-3') to regulate gene expression across multiple physiological processes 1. Functionally, USF2 acts as a transcriptional repressor of autophagy and lysosomal genes under nutrient-rich conditions by recruiting HDAC1 to CLEAR motifs, thereby reducing histone acetylation and chr19 accessibility 23. During nutrient deprivation, GSK3β-mediated phosphorylation of USF2 at serine 155 weakens its DNA binding, allowing TFEB to competitively activate these genes 3. USF2 also positively regulates genes involved in pathological processes: it transcriptionally activates THBS1 to promote TGF-β/Smad3 signaling and pyroptosis in sepsis-induced acute kidney injury 4, and activates LPCAT3 to drive ferroptosis through the NRF2/HO-1/GPX4 pathway 5. Additionally, USF2 co-regulates MSI2 expression with PLAG1 in hematopoietic stem cells, controlling stem cell self-renewal 1. Clinically, USF2 inhibition represents a therapeutic strategy for protein aggregation diseases and lysosomal dysfunction 3, and USF2 reduction of β-glucocerebrosidase activity may influence Parkinson's disease risk in GBA1 mutation carriers 6.