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However, most existing approaches focus on differential gene expression and fail to capture modular-level reorganization. Here, we present dynamic perturbation analysis (DPA), a modular rewiring framework that quantifies dynamic perturbations across disease stages using a novel metric termed the degree of perturbation. Using gastric cancer (GC) progression as a model system, DPA revealed that extensive modular rewiring persists despite limited stage-specific transcriptional changes after tumor initiation. DPA identified progression-associated perturbation programs characterized by extracellular matrix remodeling, oncogenic signaling activation, stemness acquisition, and late-stage microenvironmental adaptation. Perturbation analysis revealed two major disease-driving programs and prioritized previously unrecognized regulators, including protein tyrosine phosphatase non-receptor type 12 (PTPN12) and leucine rich repeat and Ig domain containing 1 (LINGO1), whose functional roles in GC progression were experimentally validated. Furthermore, modular rewiring-guided drug repurposing uncovered PJ-34 as a promising therapeutic candidate targeting late-stage disease-associated perturbations. Collectively, DPA provides a generalizable framework for decoding disease progression through dynamic modular rewiring, enabling the identification of driver programs, candidate regulators, and therapeutic vulnerabilities. This framework offers a scalable strategy for network-guided mechanistic discovery and therapeutic prioritization in complex diseases.<\/jats:p>","DOI":"10.1093\/bib\/bbag572","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T04:48:55Z","timestamp":1792385335000},"source":"Crossref","is-referenced-by-count":0,"title":["Dynamic perturbation analysis: a modular rewiring framework for decoding cancer stage progression and identifying therapeutic vulnerabilities"],"prefix":"10.1093","volume":"27","author":[{"given":"Bin","family":"Yang","sequence":"first","affiliation":[{"name":"Biomedical Basic Research Center (BBRC) of Jiangsu, MOE Key Laboratory of Geriatric Diseases and Immunology, School of Life Sciences, Soochow University , No. 199, Ren'ai Road, Suzhou Industrial Park, Suzhou, Jiangsu, 215123 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