ANO6 Targets TMEM30A to Regulate Endoplasmic Reticulum Stress-Induced Lipid Peroxidation and Ferroptosis in Alzheimer's Cells

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, and the role of ANO6 in its progression remains largely unexplored. GSE118553 database was analyzed for ANO6 expression in AD. A total of 1 μmol/L Aβ1-42 treated SH-SY5Y cells were constructed as a cell model of AD. qRT-PCR and ELISA were used to detect the expression of ANO6, GPX4, ATF6, GRP78, IREIα expression and lipid peroxidation level. Endoplasmic reticulum(ER) stress was induced by using clindamycin and lipid peroxidation indicators were detected. ANO6 was concurrently regulated in ER stress induced by clindamycin treatment. The STRING-DB database was utilized to predict potential target molecules of ANO6, while Western blot analysis was conducted to detect the expression levels of TMEM30A and evaluate the impact of ANO6-targeted TMEM30A on the protein levels within the PERK-eIF2α-ATF4-CHOP pathway. ANO6 was highly expressed in AD model, Aβ1-42 induced ANO6 enrichment in SH-SY5Y cells. ANO6 interference increased the proliferation level of AD model cells, decreased the levels of GPX4, an indicator of Ferroptosis, and lipid peroxidation, and down-regulated the expression of the ER stress-related proteins ATF6, GRP78, and IREIα. Clotrimazole-induced ER stress in AD model cells showed elevated expression of ANO6. ANO6 could target and inhibit TMEM30A to affect PERK-eIF2α-ATF4-CHOP pathway activity, regulate ER stress-dependent Ferroptosis, and reduce neuronal loss injury. ANO6 can target inhibition of TMEM30A affecting PERK- IF2α- ATF4- CHOP pathway activity, modulate ER stress-dependent ferroptosis-induced AD progression to reduce neuronal loss injury.

ANO6; Alzheimer’s disease; TMEM30A; ferroptosis.