Fig. 2. Excessive ER-phagy-mediated cell death.

① The transcription factors ATF4, TFEB, and TFE3 induce the expression of the ER-phagy receptors FAM134B/RETREG1 and TEX264 after pharmacological treatment, thereby initiating the ER-phagy program. Dephosphorylated CK2 phosphorylates the LIR in FAM134B and TEX264 to enhance their ability to bind LC3. The ER is cleaved into small fragments, which are wrapped by the isolation membrane and eventually degraded by lysosomes. Excessive ER consumption eventually leads to cell death. ②Excessive ER-phagy leads to the disruption of lipid and cholesterol metabolism, and lipid accumulation in lysosomes results in the accumulation of Lipid-ROS and the release of LMP, with CTSB leading to ADCD. The lysosomal receptor VCP and its cofactors YOD1, PLAA, and UBXD1 induce the degradation of damaged lysosomes to mitigate ADCD. OXPHOS provides energy for ER-phagy, and FAM134B protects mitochondria by inhibiting ROS, degrading CNX, and inhibiting Ca²⁺ conductance mediated by the IP3R-GRP75-VDAC complex. The graph was drawn with Figdraw.