Upgrading the scientific research paradigm of integrated traditional Chinese and Western medicine: from "single-target" validation to "state-target causality" validation

Over the past 7 decades, the discipline of integrated traditional Chinese and Western medicine (ITCWM) has developed a research paradigm centered on "single-target" validation. This paradigm has been highly effective in problem domains involving linear causality with a limited number of variables, but its explanatory power is increasingly constrained in more complex domains with nonlinearity and multiple interacting factors. This review summarizes the major achievements and limitations of the prevailing paradigm, examines its structural mismatch with the core problem domain of ITCWM, and proposes a "state-target causality" validation paradigm. This new paradigm focuses on establishing cross-level causal coupling between macroscopic states and microscopic events. Methodologically, it comprises 3 progressive levels—identifying, demonstrating, and applying such coupling- and a four-step research cycle: defining macroscopic phenotypes, capturing microscopic variables, verifying covariation through intervention, and reverse-validating causality. Herein this framework is used to reinterpret 3 representative lines of research: WU Yiling and colleagues' prevention and treatment of microvascular comorbidities based on the vessel-collateral theory; CHEN Xiangmei and colleagues' treatment of IgA nephropathy based on the "wind-dampness disturbing the kidney" theory; and the principle of "using poison as medicine" proposed by the research team led by ZHANG Tingdong, WANG Zhenyi, and CHEN Zhu for treatment of acute promyelocytic leukemia. These case studies illustrate how the proposed paradigm clarifies the cross-level causal logic underlying major advances in ITCWM research. Future priorities include the standardization of macroscopic phenotypes, construction of candidate target libraries, development of cross-level statistical methods, experimental reverse validation, establishment of multicenter platforms, AI-assisted applications, and broader methodological dissemination. The "state-target causality" paradigm marks the transition of ITCWM research from relying on externally derived paradigms to developing its own discipline-specific paradigm for establishing a research methodology aligned with the discipline's own problem domains.