Discovery of Monoterpenoid Indole Alkaloids Targeting CCN1 to Suppress Autophagy for the Treatment of Hypoxic Kidney Injury

Hypoxic kidney injury remains difficult to treat due to the lack of therapies that effectively prevent podocyte injury and disease progression. Bioassay-guided investigation of Tabernaemontana pandacaqui yielded ten monoterpenoid indole alkaloids (MIAs), including eight new compounds with five unprecedented carbon skeletons. Notably, compound 6 is the first MIA monomer with a 6/5/6/5/6 pentacyclic diazaspiro[acenaphthylene-3,2'-indoline]-dione core containing three nitrogen atoms. Cytoprotective screening identified 2 and 6 with nanomolar potency (EC50 ≈ 22 nM). In a chronic hypoxic kidney injury mouse model, both compounds alleviated renal injury by restoring podocyte integrity and normalizing HIF-1α, p62, and LC3-II. Integrated activity-based protein profiling, chemical proteomics, RNA sequencing, molecular docking, and functional validation identified cellular communication network factor 1 (CCN1) as the molecular target of 2. Together, these findings expand the chemical space of MIAs, establish CCN1 as a therapeutic target for hypoxic kidney injury, and identify MIAs as a promising class of renoprotective leads.