Indole-3-propionic acid exerts radio-protective effects by modulating Wnt1/STAT3 pathway to alleviate oxidative stress and neuroinflammation in microglia

Mol Immunol. 2025 Dec 22;189:192-205. doi: 10.1016/j.molimm.2025.12.011. Online ahead of print.

ABSTRACT

Radiation-induced delayed brain injury (RIBI) refers to structural and functional brain alterations that develop several months to years after exposure to ionizing radiation (IR). Microglia activation-mediated neuroinflammation, as well as oxidative stress, constitutes a key factor contributing to RIBI. Indole-3-propionic acid (IPA) is an indole metabolite specifically produced by the tryptophan metabolism of gut microbiota. It can cross the blood-brain barrier and modulate the central nervous system (CNS). In order to explore the protective mechanism of IPA on IR-induced cerebral function, we studied the effect of IPA on the activation of BV2 microglia in vitro. The experimental results show that IPA can suppress the oxidative stress and inflammation of microglia, which is represented as upregulating the expression of antioxidant genes (Hmox1, Ho-1, and Nqo1), and reducing the mRNA levels of pro-inflammatory factors (Tnf-α, Il-6, Inos, and Nox2). This protective effect may be related to the inhibition of Wnt1 expression and STAT3 phosphorylation (p-STAT3 Y705; p = 0.0008) in microglia. Additionally, it was found that IPA could alleviate the IR-induced neuroinflammation and synaptic damage of mice, as evidenced by reduced serum TNF-α and IL-6 levels and widened postsynaptic density (PSD) thickness (p = 0.0239). Collectively, this study provides novel insights into the potential application of IPA in the therapeutic intervention of radiation-induced brain injury.

PMID:41435624 | DOI:10.1016/j.molimm.2025.12.011