BIN1 and ALDH1B1 Deficiency in Colonic Smooth Muscle Drives Mitochondrial Dysfunction and Fibrosis in Slow‐Transit Constipation
Slow-transit constipation (STC) is a disabling motility disorder with unclear smooth-muscle mechanisms. Spatial proteomic analysis of STC patient colon reveals both the central pathogenic role of smooth muscle cells (SMCs) in STC and novel regulators of intestinal motility, BIN1 and ALDH1B1.
ABSTRACT
Slow-transit constipation (STC) is a disabling motility disorder with unclear smooth-muscle mechanisms. Through spatial proteomics of human colon and functional assays in primary human colonic smooth muscle cells (HCoSMCs), we identified Bridging Integrator 1 (BIN1) and Aldehyde Dehydrogenase 1B1 (ALDH1B1) as key regulators of intestinal motility. Both proteins were markedly reduced in smooth muscle from STC patients and localized to fibrotic areas. Lentiviral knockdown of BIN1 or ALDH1B1 impaired ATP-evoked Ca 2
+ responses and contraction, disrupted mitochondrial architecture, and increased reactive oxygen species. BIN1 deficiency activated mitochondrial apoptosis and extracellular matrix deposition, whereas ALDH1B1 loss induced mitophagy and NF-κB–driven inflammation. Transcriptomic and histological analyses confirmed convergence on profibrotic pathways. Together, these findings reveal a smooth-muscle-centric mechanism underlying STC pathogenesis and nominate BIN1 and ALDH1B1 as promising therapeutic entry points to restore intestinal motility.
