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Silica nanoparticles (SiNPs) have drawn considerable attention due to their environmental health effects, while enhanced understanding of metabolic disorders has provided insight into related diseases. To investigate the impacts of SiNPs exposure on reproduction and reveal their pathogenic mechanisms, this study was designed and conducted from a metabolic perspective. First, fluorescein isothiocyanate (FITC)-SiNPs were chemically synthesized and applied to track SiNPs in vitro and in vivo. Next, 30 pregnant mice were intratracheally instilled with 1.25 mg of SiNPs/mouse, then sacrificed 24 h post-treatment. We found that SiNPs penetrated the trophoblast membrane, triggering apoptosis and inhibiting cell proliferation, invasion, and tube formation in a dose-dependent manner. Mechanistically, SiNPs dysregulated phosphofructokinase (Pfkl) and fructose-bisphosphatase 2 (Fbp2) and induced glucose depletion and pyruvate accumulation via the pentose phosphate pathway. Besides, the downregulation of caspase-3 suggested a causal relationship between pyruvate accumulation, pentose phosphate pathway activation, and cell apoptosis. Pfkl and Fbp2 was also dysregulated in vivo , and the uterine inflammation aggravated in a time-dependent manner. In conclusion, SiNPs triggered acute cytotoxicity and uterine inflammation by inducing glucose depletion and pyruvate overload in trophoblasts, which were mediated in part by Pfkl and Fbp2 via the pentose phosphate pathway. [Display omitted] ● SiNP was successfully conjugated with FITC based on the Stöber method. ● SiNP could penetrate the membrane of trophoblast and induce cell dysfunction in vitro. ● SiNP induced glucose depletion and pyruvate overload in trophoblast. ● Accumulation of SiNP in the uterus triggered acute inflammation in vivo. ● The SiNP-induced reproductive toxicity was mediated via the pentose phosphate pathway. [ABSTRACT FROM AUTHOR]