Chaperone-mediated autophagy (CMA) is a selective degradation pathway that targets specific proteins for lysosomal degradation. Unlike other forms of autophagy, CMA uses a unique mechanism involving a cytosolic chaperone, HSC70, which recognizes a specific targeting motif (KFERQ) in proteins. This motif allows the protein to be translocated across the lysosomal membrane for degradation. CMA plays a crucial role in cellular processes such as glucose and lipid metabolism, DNA repair, and stress response. Recent studies have shown that CMA dysfunction with age may contribute to age-related diseases, including neurodegeneration and cancer. CMA was first discovered as a selective degradation pathway, contrasting with the bulk degradation seen in other autophagy forms. The discovery of CMA has expanded our understanding of autophagy and its role in cellular homeostasis. CMA is involved in the degradation of proteins that are either damaged or misfolded, and its failure can lead to the accumulation of toxic aggregates. CMA also contributes to the regulation of metabolic pathways by selectively degrading key enzymes, which helps maintain cellular energy balance. CMA is regulated by various factors, including the lysosomal receptor LAMP2A, which is essential for CMA function. The levels of LAMP2A can be modulated by different cellular conditions, such as oxidative stress, hypoxia, and nutrient deprivation. Additionally, signaling pathways such as NFAT and RARα signaling play a role in regulating CMA activity. The TORC2–AKT1–PHLPP1 axis also influences CMA by controlling the phosphorylation status of GFAP, which affects the stability of the CMA translocation complex. CMA has been implicated in various diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, as well as cancer. In Parkinson's disease, CMA dysfunction leads to the accumulation of toxic protein aggregates, such as α-synuclein and LRRK2. In cancer, CMA is upregulated in many tumor types and contributes to tumor growth by degrading regulatory proteins and supporting the Warburg effect. However, the role of CMA in cancer is complex, as it can both promote and inhibit tumor progression depending on the context. Overall, CMA is a critical component of cellular homeostasis and plays a vital role in maintaining protein quality control, metabolic balance, and cellular function. Understanding the mechanisms and regulation of CMA is essential for developing therapeutic strategies to treat diseases associated with CMA dysfunction.Chaperone-mediated autophagy (CMA) is a selective degradation pathway that targets specific proteins for lysosomal degradation. Unlike other forms of autophagy, CMA uses a unique mechanism involving a cytosolic chaperone, HSC70, which recognizes a specific targeting motif (KFERQ) in proteins. This motif allows the protein to be translocated across the lysosomal membrane for degradation. CMA plays a crucial role in cellular processes such as glucose and lipid metabolism, DNA repair, and stress response. Recent studies have shown that CMA dysfunction with age may contribute to age-related diseases, including neurodegeneration and cancer. CMA was first discovered as a selective degradation pathway, contrasting with the bulk degradation seen in other autophagy forms. The discovery of CMA has expanded our understanding of autophagy and its role in cellular homeostasis. CMA is involved in the degradation of proteins that are either damaged or misfolded, and its failure can lead to the accumulation of toxic aggregates. CMA also contributes to the regulation of metabolic pathways by selectively degrading key enzymes, which helps maintain cellular energy balance. CMA is regulated by various factors, including the lysosomal receptor LAMP2A, which is essential for CMA function. The levels of LAMP2A can be modulated by different cellular conditions, such as oxidative stress, hypoxia, and nutrient deprivation. Additionally, signaling pathways such as NFAT and RARα signaling play a role in regulating CMA activity. The TORC2–AKT1–PHLPP1 axis also influences CMA by controlling the phosphorylation status of GFAP, which affects the stability of the CMA translocation complex. CMA has been implicated in various diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, as well as cancer. In Parkinson's disease, CMA dysfunction leads to the accumulation of toxic protein aggregates, such as α-synuclein and LRRK2. In cancer, CMA is upregulated in many tumor types and contributes to tumor growth by degrading regulatory proteins and supporting the Warburg effect. However, the role of CMA in cancer is complex, as it can both promote and inhibit tumor progression depending on the context. Overall, CMA is a critical component of cellular homeostasis and plays a vital role in maintaining protein quality control, metabolic balance, and cellular function. Understanding the mechanisms and regulation of CMA is essential for developing therapeutic strategies to treat diseases associated with CMA dysfunction.