ER Chaperone HYOU1 Couples MAM Remodeling to Autophagic Lipid Clearance in Atherosclerosis

Endoplasmic reticulum (ER) stress and lipid accumulation are hallmarks of atherosclerosis, but their molecular crosstalk remains poorly defined. Here, we identify the ER chaperone HYOU1 as a critical regulator of mitochondria-associated membrane (MAM) remodeling and lipid homeostasis. HYOU1 is elevated in human and murine plaques and correlates with MAM-related gene networks. HYOU1 deletion disrupts MAM integrity, elevates cytosolic Ca²⁺, and induces autophagy, resulting in reduced lipid accumulation. Through phenotypic screening and chemoproteomic profiling, we identify cryptotanshinone (CTS) as a direct HYOU1-binding compound that phenocopied gene silencing by impairing MAM integrity and restoring lipid clearance. CTS reduces lipid burden and atherosclerotic plaque formation in ApoE⁻/⁻ mice. Our findings uncover a previously unrecognized ER chaperone-mediated mechanism that links MAM remodeling to lipid clearance and identify HYOU1 as a druggable target for atherosclerosis intervention.