A phenotype-to-mechanism framework links phenome-wide comorbidity architecture to molecular mechanisms and therapeutic discovery in complex diseases.

Complex human diseases exhibit substantial clinical heterogeneity driven by poorly understood molecular mechanisms, while many also lack sufficient molecular and omics data for mechanistic investigation, hindering therapeutic development. We introduce PiMInfer, a "phenotype-to-mechanism" framework that leveraged largely available real-world clinical data-based deep phenotypic characterizations with a biomedical knowledge graph approach to resolve disease clinical heterogeneity into phenotype-informed molecular modules, thereby accelerating therapeutic target discovery. We applied PiMInfer to investigate Hidradenitis Suppurativa (HS), an autoimmune skin disease with poorly understood pathogenesis and limited treatment options. PiMInfer identified a coherent, phenotype-informed HS gene module (PiHSM) and functional endotypes, which were validated using multimodal evidence. In silico drug repurposing using PiHSM prioritized Carfilzomib, targeting the immunoproteasome subunit PSMB9, essential for MHC Class I antigen presentation. Preclinical testing using human patient lesional skin explants confirmed its anti-inflammatory activity and demonstrated a significant downregulation of IFN-γ, IL-17, and mTOR signaling pathways within HS lesional microenvironment through single-cell RNA sequencing. PiHSM-based network predictions further suggest a potential enhanced efficacy of combining Carfilzomib with approved HS agents. Collectively, PiMInfer provides a scalable framework that bridges real-world phenome-wide comorbid associations to mechanism-anchored therapeutic discovery, enabling a paradigm shift in precision medicine approaches for complex diseases with limited molecular characterization and in need of better therapeutic strategies.