Xiaoxu Ding,Hui Su,Tiancong Liu,Yu Chen,Zhao Gao,Ziwen Chang,Weiliang Bai
Allergic rhinitis (AR) is an inflammatory disease of the upper airway that primarily affects the nasal mucosa, with Th2 differentiation-driven inflammation as a key contributor. A bioinformatics analysis of dataset GSE52804 identified Six-transmembrane epithelial antigen of prostate 4 (STEAP4), a metalloreductase involved in inflammation regulation, as associated with AR progression, though its specific function remains unclear. Data obtained from nasal mucosal tissues from AR patients ( n = 13) and an ovalbumin (OVA)-induced AR mouse model demonstrated a marked upregulation of STEAP4. Subsequent loss-of-function experiments revealed that STEAP4 knockdown reduced Th1/Th2 imbalance-mediated inflammation, alleviating allergic symptoms in OVA-treated mice. Further investigations involved the purification of naïve CD4 + T cells from healthy murine splenocytes and their Th2 polarization. Consistently, STEAP4 knockdown inhibited Th2 differentiation and the production of Th2-related cytokines in vitro. Additionally, Guanine adenine thymine adenine sequence-binding protein 3 (GATA3), a transcription factor essential for Th2 differentiation, was predicted to bind to the STEAP4 promoter. CHIP-PCR and dual-luciferase assays confirmed the transcriptional regulation of STEAP4 by GATA3. More importantly, STEAP4 knockdown rescued the promoting effects of GATA3 overexpression on Th2 differentiation. In conclusion, STEAP4 functions downstream of GATA3 to promote AR development by promoting Th2 differentiation-mediated inflammation, suggesting its potential as a target for AR treatment.
Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu + ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.
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