Post-translational modifications of selective autophagy receptors: orchestrating cellular homeostasis, disease pathogenesis, and therapeutic opportunities

Selective autophagy, an evolutionarily conserved quality control process, preserves cellular homeostasis by degrading specific substrates or organelles. Autophagy receptors, which precisely recognize and target substrates through sophisticated molecular mechanisms, are central to this pathway. These receptors orchestrate diverse biological functions ranging from DNA damage response, protein degradation, proteostasis, neuronal health, to immune modulation. Increasing evidence suggests that posttranslational modifications (PTMs) critically regulate the biological functions of autophagy receptors, forming a complex regulatory network that remains incompletely characterized in disease pathogenesis. This review first summarizes current knowledge of mammalian autophagy, including the principal molecular machinery across diverse pathways. We then categorize autophagy receptors on the basis of cargo specificity, and highlight PTM-mediated regulatory mechanisms. Furthermore, we explore their pathophysiological roles and assess their therapeutic potential by integrating recent advances. Finally, we discuss emerging perspectives in the autophagy research field, especially for the discovery of pathology-associated PTMs that modulate the functions of autophagy receptors. A deeper understanding of autophagic regulation and its pathophysiological significance will advance innovative therapeutic strategies targeting diseases associated with autophagy dysfunction.