STAT3 inhibitors(Zhejiang Chinese Medical University)

Inhibition of malignant transformation from the precancerous stage has important clinical value for the prevention of gastric cancer. Here, we report a strategy to inhibit precancerous gastric conditions by Luteolin (Lut). Lut treatment resulted in remarkable resistance to oxyntic atrophy, spasmolytic polypeptide-expressing metaplasia (SPEM), and gastric mucosal injury in tamoxifen (TAM)-treated mice, chenodeoxycholic acid-treated rats, and human organoids. Mechanism study suggested that LCN2 expression was upregulated in the SPEM mucosa and downregulated after Lut treatment. LCN2 blocking suppressed TAM-induced oxyntic atrophy and metaplasia and partially counteracted the effect of Lut. Quantitative chemoproteomics identified that Lut bound to STAT3 and inhibited its phosphorylation. Functional experiments using STAT3 inhibitors and epithelial cell-specific Stat3 deficient mice showed that STAT3 inhibition and deletion attenuated the beneficial effects of Lut. Our data supported that Lut might be a therapeutic candidate for the treatment of gastric mucosal injury by binding to STAT3 and thereby inhibiting the STAT3/LCN2 axis.

Psoriasis is a prevalent chronic inflammatory skin disease characterized by immune cell activation and aberrant keratinocyte proliferation. Signal transducer and activator of transcription 3 (STAT3) plays a key role in the pathology of psoriasis, positioning it as a promising target for therapeutic strategies. However, current STAT3 inhibitors often lack specificity, leading to adverse effects. Here, we present the development of dendritic lipopeptides (DLPs) designed to facilitate the transdermal delivery of small interfering RNA (siRNA) to specifically inhibit STAT3 expression in psoriatic lesions. The dendritic architecture and peptide composition of DLP are crucial for interaction with keratin of stratum corneum and gene transfection efficiency, while the lipid chain selection aims to increase lipophilicity and enhance interactions with cellular membranes. We conducted extensive in vitro and in vivo investigations to assess the therapeutic efficacy of these DLPs for siRNA delivery in psoriasis treatment. The results demonstrated that our DLPs effectively penetrated the skin barrier, delivered siRNA to target cells, and significantly reduced STAT3 expression, regulated immune cell imbalance, leading to a marked improvement in psoriasis symptoms. In conclusion, our study presents a promising non-invasive approach to psoriasis treatment by focusing on the targeted suppression of STAT3 expression. The dendritic lipopeptides offer a safe and effective platform of siRNA delivery, potentially revolutionizing the management of psoriasis and other chronic inflammatory dermatological conditions.