Indoxyl sulfate–associated vascular calcification is linked to mTORC1 and ER stress–integrated stress response signaling

Medial vascular calcification is a major cardiovascular complication of chronic kidney disease (CKD), with the uremic toxin indoxyl sulfate (IS) implicated in its pathogenesis. However, the molecular mechanisms by which IS promotes vascular calcification remain incompletely understood. In human aortic smooth muscle cells (hASMCs), IS induced oxidative stress and stimulated the MEK–ERK1/2 and PI3K–AKT signaling pathways, leading to mTORC1 activation. This led to impaired autophagy, endoplasmic reticulum (ER) stress, and activation of the integrated stress response (ISR). Collectively, these alterations drove osteochondrogenic transdifferentiation, cellular senescence, and calcium deposition in hASMCs, processes that were further exacerbated by elevated phosphate. Pharmacological intervention with nicotinamide mononucleotide (NMN) or tauroursodeoxycholic acid (TUDCA) attenuated ER stress–ISR signaling and suppressed osteogenic and senescence-associated markers under IS and phosphate conditions. Collectively, these findings identify mTORC1-ER stress–ISR signaling as a central mechanism linking IS to vascular calcification and highlight this pathway as a promising therapeutic target for CKD-associated vascular disease.