Clockophagy pathway

Clockophagy is a specialized form of selective autophagy responsible for the targeted degradation of the core circadian clock protein Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), commonly known as BMAL1 (Yang et al., 2019, PMID: 31113318). This pathway is primarily mediated by the cargo receptor Sequestosome-1 (SQSTM1/p62), which binds to BMAL1 and directs it to the autophagosome for subsequent lysosomal digestion (Tang et al., 2019, PMID: 31202533). By regulating the turnover of BMAL1, clockophagy serves as a critical link between the cellular molecular clock and metabolic processes, as well as cell death pathways. Research has highlighted its significant role in ferroptosis, where the degradation of BMAL1 enhances cellular sensitivity to iron-dependent oxidative stress, particularly in cancer cells (Yang et al., 2019, PMID: 31113318). Consequently, the clockophagy pathway is being explored as a therapeutic target for sensitizing tumors to treatment and managing circadian-related pathologies. However, pharmacological intervention must be carefully managed to avoid broad disruption of the body's internal timing systems and systemic circadian rhythms.

Other names

Selective autophagy of BMAL1BMAL1 degradation pathwayCircadian clock autophagyARNTL-selective autophagyBMAL1-p62-LC3 axis

The pathway involves the SQSTM1-mediated recognition and sequestration of the BMAL1 protein into autophagosomes for lysosomal degradation, which modulates circadian gene expression and increases cellular sensitivity to ferroptosis (Yang et al., 2019, PMID: 31113318).