# ShenQi DiHuang Decoction (SQDHD) Ameliorates Neuroinflammation and Neuropsychiatric Manifestations in Pristane Induced Lupus Mice via Blocking JAK1‐STAT3 Pathway

## TL;DR

This study shows that ShenQi DiHuang Decoction (SQDHD) reduces brain inflammation and behavioral issues in lupus mice by blocking the JAK1-STAT3 pathway.

## Contribution

The study is the first to demonstrate SQDHD's neuroprotective effects in NPSLE and identifies its mechanism via JAK1-STAT3 inhibition.

## Key findings

- SQDHD reduced anxiety, depression, and olfactory dysfunction in pristane-induced lupus mice.
- SQDHD compounds like Alisol B acetate and Hederagenin inhibited JAK1-STAT3 signaling in cerebrovascular endothelial cells.
- SQDHD decreased BBB leakage, cytokine overexpression, and immunoglobulin G deposition in the brain.

## Abstract

Neuroinflammation is widely acknowledged as a crucial pathogenic factor in neuropsychiatric systemic lupus erythematosus (NPSLE). However, specific clinical treatments to mitigate neuroinflammation associated with NPSLE are currently lacking. While ShenQi DiHuang decoction (SQDHD) has demonstrated significant anti‐inflammatory effects in lupus nephritis, its efficacy in NPSLE has yet to be investigated. This study aims to explore the neuroprotective effects of SQDHD in NPSLE and to elucidate the underlying mechanisms.

In vivo, the effects of SQDHD were studied in pristane‐induced lupus (PIL) mice using behavioral tests, intravital microscopy, blood–brain barrier (BBB) permeability assessment, cytokine quantification, and brain histopathological analysis. The active compounds and the underlying mechanism of SQDHD action against NPSLE were examined using ultra performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS), network pharmacology, molecular docking, cellular thermal shift assays (CETSAs), and drug affinity responsive target stability (DARTS) assays. In vitro and in vivo experiments were performed to validate the proposed mechanism.

SQDHD significantly ameliorated olfactory dysfunction, anxiety, and depression in PIL mice. Additionally, adhesion molecule upregulation, leukocyte recruitment, BBB leakage, and brain pathophysiological alterations, including cytokine overexpression, immunoglobulin G deposition, and lipofuscin accumulation were markedly reduced. By integrating UPLC‐MS/MS, network pharmacology, and molecular docking, we predicted the therapeutic mechanism of SQDHD against NPSLE to involve Janus kinase‐signal transducer and activator of transcription (JAK–STAT) signaling. Five primary active compounds of SQDHD, Alisol B acetate, Hederagenin, Ellagic acid, Wogonin, and Quercetin, exhibited strong binding affinities to JAK1 and other JAK–STAT pathway components, surpassing the binding affinities of Upadacitinib, a selective JAK1 inhibitor. CETSAs and DARTS assays confirmed the direct interactions between these compounds and JAK1. Alisol B acetate and Hederagenin inhibited the JAK1‐STAT3 pathway and its downstream effectors in cerebrovascular endothelial cells (CVECs). In vitro studies in lupus serum‐induced CVECs and in vivo studies in PIL mice further corroborated SQDHD downregulation of elevated levels of adhesion molecules, potentially through inhibition of JAK1‐STAT3 signaling.

SQDHD may exert neuroprotective effects in NPSLE by inhibiting the activation of CVECs through blocking the JAK1‐STAT3 signaling pathway, thereby suggesting its potential as a promising therapeutic strategy for NPSLE.

SQDHD exerts neuroprotective effects and alleviates behavioral deficits in PIL mice, likely by inhibiting the JAK1‐STAT3 pathway in activated CVECs. These findings underscore the therapeutic potential of SQDHD and establish it as a promising candidate for the treatment of NPSLE.