• FAM134B-mediated excessive ER-phagy is linked to trophoblast mitochondrial dysfunction in preeclampsia.
• Increased FAM134B, IP3R, calnexin, cleaved caspase 3, and cytochrome C are observed in PE placentas and SNP-treated trophoblast cells.
• Overexpression of FAM134B impairs trophoblast invasion and mitochondrial function, while autophagy inhibition rescues mitochondrial performance.
• Excessive ER-phagy is associated with elevated gamma linolenic acid, suggesting a lipidomic link in PE pathogenesis.