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Sijunzi Decoction (SJZD) is a renowned formula for the treatment of spleen deficiency syndrome (SDS) in traditional Chinese medicine (TCM). Its non-polysaccharides (NPS) component, dominated by various compounds of SJZD, has shown the remarkable efficacy in SDS, especially in gastrointestinal injury. However, the principle of compatibility of SJZD and the micro-mechanism of effect on SDS are still unclear. To elucidate the scientific implications of SJZD compatibility and its micro-mechanism in the treatment of SDS-induced intestinal injury. First, the chemical composition of NPS in SJZD and incomplete SJZD (iSJZD, including SJZD-R, SJZD-A, SJZD-P, SJZD-G) were comprehensively analyzed by UPLC-QTOF-MS, and comparing their chemical composition by multivariate statistical analysis to reveal the effect of a single herb on SJZD compatibility. Second, network pharmacology and molecular docking were used to uncover the micro-mechanisms of potential active compounds in SJZD for the treatment of SDS, and develop an active component combination (ACC) by accurate quantification. Subsequently, the action of the potential active compounds and ACC was verified through in vivo and in vitro. A total of 112, 77, 93, 87, and 67 compounds were detected in NPS of SJZD, SJZD-R, SJZD-A, SJZD-P, and SJZD-G, respectively. Changes in the chemical components of SJZD_NPS and iSJZD_NPS revealed that RG and RAM, as well as RAM and Poria significantly affected the dissolution of each other's chemical components, and the co-decoction of four herbs promoted the dissolution of the active compounds and inhibited toxic compounds. Furthermore, network pharmacology showed that 274 compounds of 15 categories in SJZD_NPS acted on the 186 key targets to treat SDS by inhibiting inflammation, enhancing immunity, and regulating gastrointestinal function and metabolism. Finally, through in vitro experiments, six compounds among 18 potential compounds were verified to markedly repair intestinal epithelium injury by modulating the FAK/PI3K/Akt or LCK/Ras/PI3K/Akt signaling pathway. It is worth mentioning that ACC, composed of 11 compounds accurately quantified, demonstrated significant in vivo treatment effects on intestinal damage with SDS similar to NPS or SJZD. This study elucidates the scientific evidence of the " Jun-Chen-Zuo-Shi " and "detoxification and synergistic" in the decocting process of SJZD. An ACC, the active component of SJZD, ameliorate SDS-induced intestinal injury by the FAK/PI3K/Akt signaling pathway, which provides a strategy for screening alternatives to effective combinations of TCMs. [Display omitted] • Uncovering the principle of "Jun-Chen-Zuo-Shi" and "detoxification and synergistic" of four herbs in SJZD. • Various types of compounds in SJZD_NPS treat SDS through inhibiting inflammation, enhancing immunity, and regulating metabolism and gastrointestinal function. • Six potential active compounds and active component combination repaired the SDS with intestinal injury via modulating FAK/PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]