Unraveling the Gut Microbiota–SCFAs–Cathepsin C Pathway in Preeclampsia: A Novel Therapeutic Target

Fan Lu¹Houkang Lei¹Xiang Xiao¹Luzhu Yu^2*

• ¹The Affiliated Hospital of Guizhou Medical University, Guiyang, China
• ²Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, China

Preeclampsia (PE) is a serious obstetric syndrome characterized by impaired maternal-fetal immunological tolerance, placental insufficiency, and systemic inflammatory activation. Emerging evidence highlights the involvement of gut microbial communities and their breakdown products, especially short-chain fatty acids (SCFAs), in the progression of PE. Through a combination of clinical data and experimental models, this work examines how SCFAs influence cathepsin C expression and their subsequent effects on disruptions in the maternal-fetal immune milieu in PE. Our findings indicate significant gut microbiota alterations in PE patients, including a decline in SCFA-producing bacterial populations and an expansion of inflammatory microbes, collectively resulting in reduced SCFA biosynthesis. Clinically, SCFA concentrations were inversely correlated with cathepsin C expression, which itself was positively linked to hypertension and proteinuria. In vivo, SCFA supplementation markedly suppressed placental cathepsin C levels and improved hallmark PE phenotypes such as elevated blood pressure, proteinuria, and impaired fetal growth. Moreover, cathepsin C overexpression abolished the beneficial effects of SCFAs and worsened PE progression. At the mechanistic level, SCFAs downregulate cathepsin C, promoting a shift in macrophage polarization toward the M2 anti-inflammatory phenotype, which helps reestablish immune regulation at the maternal-fetal boundary. This research unveils the "gut microbiota–SCFAs–cathepsin C–macrophage polarization" pathway as a pivotal element in PE etiology, providing new avenues for early detection, stratification, and precision interventions.